Compounds with activity at estrogen receptors

ABSTRACT

Disclosed herein are novel di-aromatic compounds and methods for using various di-aromatic compounds for treatment and prevention of diseases and disorders related to estrogen receptors.

RELATED APPLICATION

This application is a continuation-in-part of U.S. application Ser. No.11/120,397, filed May 3, 2005, entitled “COMPOUNDS WITH ACTIVITY ATESTROGEN RECEPTORS,” which claims priority to U.S. ProvisionalApplication No. 60/568,332, filed May 4, 2004, entitled “IDENTIFICATIONOF COMPOUNDS WITH ACTIVITY ON ESTROGEN RECEPTORS,” both of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to the fields of organic chemistry,pharmaceutical chemistry, biochemistry, molecular biology and medicine.In particular it relates to compounds that modulate the activity of theEstrogen receptors, and to the use of the compounds for the treatmentand prevention of diseases and disorders related to the Estrogen betareceptor.

DESCRIPTION OF THE RELATED ART

Estrogen receptors (ER) belong to the family of nuclear hormonereceptors. Nuclear hormone receptors define a superfamily of ligandactivated transcription factors (Evans, 1988, Science 240:889). Membersof this family are typically characterized by the presence of conservedmodular domains: a zinc finger DNA binding domain (DBD) triggers theinteraction of the receptor with specific response elements at the DNAsite, a ligand binding domain (LBD) adjacent to the DBD, and twotranscriptional activation domains AF-1 and AF-2 ligand-independent andligand-dependent, respectively (Nilsson, 2002, SERMs: Research andclinical applications, Eds: Humana Press Inc, 3). Upon ligand binding tothe receptor, a conformational change occurs within the LBD bringing theAF-2 domain in closer proximity and allowing for the recruitment ofco-activators. Co-activators create a physical interaction between thenuclear hormone receptor and components of the transcriptionalmachinery, establishing transcriptional modulation of target genes.

Two estrogen receptor subtypes have been identified: ER alpha (ERα,NR3A1) (Green, 1986, Nature 320:134; Greene, 1986, Science 231:1150) andER beta (ERβ, NR3A2) (Kuiper, 1996, PNAS 93:5925). Both receptors bindto the endogenous natural ligand 17β estradiol with comparable highaffinity and modulate the transcriptional activity of target genesthrough classical estrogen response elements (reviewed in Nilsson, 2005,Bas Clin Pharm Tox, 96:15). More recently, it has been demonstrated thatestrogen receptors can mediate non classical actions (reviewed inOsborne, 2005, J Clin Oncol 8:1616): (1) non classical transcriptionalregulation in which ERs function as co-activators on alternateregulatory DNA sequences, (2) non genomic or membrane-initiated steroidsignaling in which ERs evoke rapid cytoplasmic signaling, and (3)crosstalk with Receptor Tyrosine Kinases (RTKs). Interestingly enough,their ligand binding domains (LBD) only share 56% amino acid identitywhich suggest that they might accommodate different ligands and thusmediate different or even opposite effects (Kuiper, 1997, FEBS Lett,410:87). Moreover, the distribution pattern of the two receptors isquite different (reviewed in Mathews, 2003, Mol Interv 3:281). Both ERsare widely distributed both peripherally and in the brain, displayingdistinct and sometimes overlapping patterns in a variety of tissues. ERαis expressed primarily in the uterus, liver, kidney and heart. On theother hand ERβ is present mainly in the ovary, prostate, lung,gastrointestinal tract, bladder, hematopoietic and central nervoussystem (CNS). ERβ specific localization in the CNS includes thehippocampus and thalamus (Osterlund, 2001, Prog Neurobiol 64:251;Ostlund, 2003, Ann NY acad Sci 1007:54). ERα and ERβ are co-expressed inthe mammary gland, epididymis, thyroid, adrenal, bone and the dorsalroot ganglia of the spinal cord and the cerebral cortex of the brain.

The characterization of mice lacking ERα or ERβ has provided insightinto the physiology of estrogen receptors (reviewed in Hewitt, 2000,Breast Cancer Res 2:345; Couse, 1999, Endoc Rev 20:358). Both ERα maleand female null mice are infertile because of dysfunction inspermatogenesis and ovulation, respectively. In addition, null femalesdisplay a lack of sexual behavior, increased aggression and infanticide.Null male exhibit normal mounting behavior but a complete lack ofintromission and ejaculation. They also show reduced aggression. Incontrast, ERβ null female mice are subfertile with reduced littermates.Male counterparts show no apparent defects in their reproductive tract.The neuroendocrine system is significantly altered in ERα null mice incontrast to ERβ null mice which do not show any impairment. Moreover,the knock-out of ERα in mice leads to absence of breast tissuedevelopment, lower bone density and impaired glucose tolerance. Knockout studies of ERβ led to controversial results with some studies beingunable to see an effect on bone density (Lindberg, 2002, J Bone Min Res17:555), whereas other reports suggested an increase in trabecular bonevolume in females only due to decreased bone resorption (reviewed inWindahl, 2002, Trends Endoc Metab, 13:195). Interestingly enough,morphological alterations in the brains of mice lacking ERβ are evident(Wang, 2001, PNAS 98:2792) associated with impaired neuronal survival(Wang, 2003, PNAS 100:703), and lead to speculate that ERβ could have animportant role in protecting from neurodegenerative disorders such asAlzheimer and Parkinson diseases, and potentially from those resultingof trauma and cardiovascular insults. This is further supported byexperimental studies indicating a neurotrophic and neuroprotective rolefor estrogens (reviewed in Wise, 2002, Trends Endocrinol Metab 13:229;Behl, 2003, J Steroid Biochem Mol Biol 83:195).

More recently, the use of a relatively selective ERβ agonist hasunraveled a prominent role in inflammation for this subtype (Harris,2003, Endoc 144:4241). Beneficial effects were seen in animal models ofinflammatory bowel disease and adjuvant-induced arthritis. Indeed, ERβis expressed both in the intestine and in immune cells. Moreover, ERβnull studies have suggested a role in thymus function (Erlandsson, 2001,Immunol 103:17) as well as in pulmonary inflammation (Patrone, 2003, MolCell Biol 25:8542). Interestingly though, no effects associated withclassical estrogen function was evident through the use of this ERβagonist (Harris, 2003, Endoc 144:4241). In particular, that ligand wasinactive in mammotrophy, bone density and ovulation in vivo assays. Thisdata is to a certain extent in contrast to a variety of studiesincluding human polymorphisms, knock-out animals, tissue distribution,that argue for a role of ERβ in bone and ovulation homeostasis. Othertherapeutic roles for selective ERβ agonists have also been proposedincluding prostate and breast cancer, autoimmune diseases, colon cancer,malignancies of the immune system, neurodegeneration, cardiovascularfunction, bone function (reviewed in Koehler, 2005, Endocr Reviews, DOI10.1210).

SUMMARY OF THE DISCLOSURE

One embodiment disclosed herein is a compound of formula (I):

-   -   or a pharmaceutically acceptable salt or prodrug thereof,        wherein:    -   n is an integer selected from the group consisting of 3, 4, 5        and 6;    -   R₁ is selected from the group consisting of hydrogen, C₁-C₈        straight chained or branched alkyl, C₁-C₈ straight chained or        branched alkenyl, cycloalkyl, cycloalkenyl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroalicyclyl, sulphonyl, C₁-C₈        straight chained or branched perhaloalkyl, —C(═Z)R₆, —C(═Z)OR₆,        —C(═Z)N(R₆)₂, —S(═O)₂NR_(5a)R_(5b), —P(═O)(OR₆)₂, and        —CH₂OC(═O)R₅;    -   R₂, R_(2a), R_(2b), R_(2c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, halogen, sulfonyl, perhaloalkyl, —CN,        —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b), —NR₆N═CR_(6a)R_(6b),        —N(R₆)C(R_(6a))═NR_(6b), —C(═Z)R₆, —C(═Z)OR₆, —C(═Z)NR₆R_(6a),        —N(R₆)—C(═Z)R_(6a), —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆,        —N(R₆)—S(═O)₂R_(6a), and —SR₆;    -   each R₃ is separately selected from the group consisting of        hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted        or unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heteroalicyclyl, hydroxy, halogen,        sulfonyl, perhaloalkyl, —CN, ═O, and —OR₆, or are separately        absent to accommodate a double bond;    -   two R₃ groups are optionally bound together to form a        substituted or unsubstituted C₃-C₉ cycloalkyl or C₃-C₉        heteroalicyclyl;    -   R_(2a) is optionally bound to one R₃ group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   R_(4a) is optionally bound to one R₃ group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   any bond represented by a dashed and solid line represents a        bond selected from the group consisting of a single bond and a        double bond;    -   R₄, R_(4a), R_(4b), R_(4c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, nitro, halogen, sulfonyl,        perhaloalkyl, —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b),        —NR₆N═CR_(6a)R_(6b), —N(R₆)C(R_(6a))═NR_(6b), —CN, —C(═Z)R₆,        —C(═Z)OR₆, —C(═Z)NR₆R_(6a), —S(═Z)NR₆R_(6a), —N(R₆)—C(═Z)R_(6a),        —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆, —N(R₆)—S(═O)₂R_(6a), and        —SR₆;    -   R_(4a) and R_(4b) are optionally bound together to form an aryl,        heteroaryl, or heteroalicyclyl;    -   R₅ is selected from the group consisting of hydrogen, alkyl,        alkenyl, cycloalkyl, cycloalkenyl, halogen, —CN, —SR₆, sulfonyl,        —C(═O)NR₆R_(6a), —C(═O)R₆, —NR₆R_(6a), —COOR₆, and perhaloalkyl;    -   Z is oxygen or sulfur; and    -   R₆, R_(6a) and R_(6b) are separately selected from the group        consisting of hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted cycloalkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, and        substituted or unsubstituted heteroalicyclyl;    -   provided that the compound is not selected from the group        consisting of:

In some embodiments of the compound of formula I, n is an integerselected from the group consisting of 3, 4, and 5; R₁ is selected fromthe group consisting of hydrogen, C₁-C₄ straight chained or branchedalkyl, C₁-C₄ straight chained or branched alkenyl, C₁-C₄ straightchained or branched perhaloalkyl, substituted or unsubstituted aryl,—(C═O)R₆, —S(═O)₂NR_(5a)R_(5b), —P(═O)(OR₆)₂, and —CH₂OC(═O)R₅; R₂,R_(2a), R_(2b), R_(2c) are separately selected from the group consistingof hydrogen, C₁-C₅ straight chained or branched alkyl, C₁-C₅ alkenyl,hydroxy, halogen, sulfonyl, perhaloalkyl, —CN, —OR₆, —C(═O)R₆,—C(═O)OR₆, —C(═O)NR₆R_(6a), —N(R₆)—C(═O)R_(6a), —N(R₆)—S(═O)₂R_(6a),—OC(═O)R₆, and —SR₆; each R₃ is separately selected from the groupconsisting of hydrogen, C₁-C₅ straight chained or branched alkyl, C₁-C₅alkenyl, cycloalkyl, cycloalkenyl, hydroxy, halogen, sulfonyl,perhaloalkyl, —CN, ═O, and —OR₆, or each R₃ is separately absent toaccommodate a double bond; R₄, R_(4a), R_(4b), R_(4c) are separatelyselected from the group consisting hydrogen, C₁-C₅ straight chained orbranched alkyl, C₁-C₅ alkenyl, hydroxy, halogen, sulfonyl, perhaloalkyl,—OR₆, —CN, —C(═O)R₆, —C(═O)OR₆, —C(═O)NR₆R_(6a), —S(═O)₂NR₆R_(6a),—N(R₆)—C(═O)R_(6a), —OC(═Z)R₆, —N(R₆)—S(═O)₂R_(6a), and —SR₆; and R₅ isselected from the group consisting of hydrogen, C₁-C₅ straight chainedor branched alkyl, halogen, —CN, —SR₆, sulfonyl, and perhaloalkyl. Inone of these embodiments, R₁ is selected from the group consiting of—(C═O)R₆, —S(═O)₂NR_(5a)R_(5b), —P(═O)(OR₆)₂, and —CH₂OC(═O)R₅

In another embodiment of the compound of formula I, n is 3; R₁ isselected from the group consisting of hydrogen, C₁-C₅ straight chainedor branched alkyl, substituted or unsubstituted aryl, —(C═O)R₆,—S(═O)₂NR_(5a)R_(5b), —P(═O)(OR₆)₂, and —CH₂OC(═O)R₅; R₂, R_(2a),R_(2b), R_(2c) are separately selected from the group consisting ofhydrogen, C₁-C₅ straight chained or branched alkyl, F, Cl, Br,perhaloalkyl, —CN, —OR₆, and —SR₆; each R₃ is separately selected fromthe group consisting of hydrogen, C₁-C₅ straight chained or branchedalkyl, C₁-C₅ alkenyl, cycloalkyl, halogen, perhaloalkyl, —CN, and —OR₆,or each R₃ is separately absent to accommodate a double bond; each R₄,R_(4a), R_(4b), R_(4c) is separately selected from the group consistinghydrogen, C₁-C₅ straight chained or branched alkyl, halogen, sulfonyl,perhaloalkyl, —OR₆, —CN, —N(R₆)—S(═O)₂R_(6a), and —SR₆; and R₅ isselected from the group consisting of hydrogen, C₁-C₅ straight chainedor branched alkyl, F, Cl, —CN, —SR₆, and CF₃.

In another embodiment of the compound of formula I, R₁ is hydrogen. Instill another embodiment of the compound of formula I, R₅ is hydrogen orhalogen.

In various embodiments, the compound of formula I is selected from thegroup consisting of:

or a pharmaceutically acceptable salt or prodrug thereof.

Another embodiment disclosed herein is a pharmaceutical composition,comprising a pharmaceutically acceptable amount of a compound of formulaI.

Another embodiment disclosed herein is a method of treating orpreventing disorders selected from the group consisting of inflammatorybowel syndrome; Crohn's disease; ulcerative proctitis or colitis;prostatic hypertrophy; uterine leiomyomnas; breast carcinoma;endometrial carcinoma; polycystic ovary syndrome; endometrial polyps;benign breast disease; adenomyosis; ovarian carcinoma; melanoma;prostate carcinoma; colon carcinoma; brain tumors includingglioblastoma, astrocytoma, glioma, or meningioma; prostatitis;interstitial cystitis; bone density loss including osteoporosis orosteopenia; discholesterolemia; dislipidemia; cardiovascular disease;atherosclerosis; hypertension; peripheral vascular disease; restenosis;vasospasm; neurodegenerative disorders including Alzheimer's disease,Huntington's disease, Parkinson's disease or other dementias; spinalcord injury; cognitive decline; stroke; anxiety; vaginal atrophy; vulvaratrophy; atrophic vaginitis; vaginal dryness; pruritus; dyspareunia;frequent urination; urinary incontinence; urinary tract infections;vasomotor symptoms including flushing or hot flashes; arthritisincluding rheumatoid arthritis, osteoarthritis, orarthropathiesendometriosis; psoriasis; dermatitis; asthma; pleurisy;multiple sclerosis; systemic lupus erthematosis; uveitis; sepsis;hemmorhagic shock; type II diabetes; acute or chronic inflammation; lungdisorders including asthma or chronic obstructive pulmonary disease;ophthalmological disorders including glaucoma, dry eye, or maculardegeneration; and free radical induced disease states; including:

-   -   identifying a subject in need of the treating or preventing; and    -   administering to the subject a pharmaceutically effective amount        of a compound of formula I:

-   -   or a pharmaceutically acceptable salt or prodrug thereof,        wherein:    -   n is an integer selected from the group consisting of 3, 4, 5        and 6;    -   R₁ is selected from the group consisting of hydrogen, C₁-C₈        straight chained or branched alkyl, C₁-C₈ straight chained or        branched alkenyl, cycloalkyl, cycloalkenyl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroalicyclyl, sulphonyl, C₁-C₈        straight chained or branched perhaloalkyl, —C(═Z)R₆, —C(═Z)OR₆,        —C(═Z)N(R₆)₂, —S(═O)₂NR_(5a)R_(5b), —P(═O)(OR₆)₂, and        —CH₂OC(═O)R₅;    -   R₂, R_(2a), R_(2b), R_(2c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, halogen, sulfonyl, perhaloalkyl, —CN,        —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b), —NR₆N═CR_(6a)R_(6b),        —N(R₆)C(R_(6a))═NR_(6b), —C(═Z)R₆, —C(═Z)OR₆, —C(═Z)NR₆R_(6a),        —N(R₆)—C(═Z)R_(6a), —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆,        —N(R₆)—S(═O)₂R_(6a), and —SR₆;    -   each R₃ is separately selected from the group consisting of        hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted        or unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heteroalicyclyl, hydroxy, halogen,        sulfonyl, perhaloalkyl, —CN, ═O, and —OR₆, or are separately        absent to accommodate a double bond;    -   two R₃ groups are optionally bound together to form a        substituted or unsubstituted C₃-C₉ cycloalkyl or C₃-C₉        heteroalicyclyl;    -   R_(2a) is optionally bound to one R₃ group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   any bond represented by a dashed and solid line represents a        bond selected from the group consisting of a single bond and a        double bond;    -   R₄, R_(4a), R_(4b), R_(4c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, nitro, halogen, sulfonyl,        perhaloalkyl, —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b),        —NR₆N═CR_(6a)R_(6b), —N(R₆)C(R_(6a))═NR_(6b), —CN, —C(═Z)R₆,        —C(═Z)OR₆, —C(═Z)NR₆R_(6a), —S(═Z)NR₆R_(6a), —N(R₆)—C(═Z)R_(6a),        —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆, —N(R₆)—S(═O)₂R_(6a), and        —SR₆;    -   R_(4a) and R_(4b) are optionally bound together to form an aryl,        heteroaryl, or heteroalicyclyl;    -   R₅ is selected from the group consisting of hydrogen, alkyl,        alkenyl, cycloalkyl, cycloalkenyl, halogen, —CN, —SR₆, sulfonyl,        C(═O)NR₆R_(6a), —C(═O)R₆, —NR₆R_(6a), —COOR₆, and perhaloalkyl;    -   Z is oxygen or sulfur; and    -   R₆, R_(6a) and R_(6b) are separately selected from the group        consisting of hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted cycloalkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, and        substituted or unsubstituted heteroalicyclyl.

In some embodiments, the disorder is selected from the group consistingof inflammatory bowel syndrome, Crohn's disease, and ulcerativeproctitis or colitis.

In some embodiments, the disorder is selected from the group consistingof prostatic hypertrophy, uterine leiomyomnas, breast carcinoma,endometrial carcinoma, polycystic ovary syndrome, endometrial polyps,benign breast disease, adenomyosis, ovarian carcinoma, melanoma,prostate carcinoma, colon carcinoma, and brain tumors includingglioblastoma, astrocytoma, glioma, or meningioma.

In some embodiments, the disorder is selected from the group consistingof prostatitis and interstitial cystitis.

In some embodiments, the disorder is bone density loss includingosteoporosis and osteopenia.

In some embodiments, the disorder is selected from the group consistingof dicholesterolemia and dislipidemia.

In some embodiments, the disorder is selected from the group consistingof cardiovascular disease, atherosclerosis, hypertension, peripheralvascular disease, restenosis and vasospasm.

In some embodiments, the disorder is a neurodegenerative disorderincluding Alzheimer's disease, Huntington's disease, Parkinson's diseaseor other dementia.

In some embodiments, the disorder is a spinal cord injury.

In some embodiments, the disorder is selected from the group consistingof cognitive decline, stroke, and anxiety.

In some embodiments, the disorder is selected from the group consistingof vaginal atrophy, vulvar atrophy, atrophic vaginitis, vaginal dryness,pruritus, dyspareunia, frequent urination, urinary incontinence, andurinary tract infections.

In some embodiments, the disorder is one or more vasomotor symptomsincluding flushing or hot flashes.

In some embodiments, the disorder is endometriosis.

In some embodiments, the disorder is arthritis including rheumatoidarthritis, osteoarthritis, or arthropathies.

In some embodiments, the disorder is selected from the group consistingof psoriasis and dermatitis.

In some embodiments, the disorder is selected from the group consistingof asthma and pleurisy.

In some embodiments, the disorder is selected from the group consistingof multiple sclerosis, systemic lupus erthematosis, uveitis, sepsis, andhemmorhagic shock.

In some embodiments, the disorder is type II diabetes.

In some embodiments, the disorder is selected from the group consistingof acute and chronic inflammation.

In some embodiments, the disorder is a lung disorders including asthmaor chronic obstructive pulmonary disease.

In some embodiments, the disorder is an ophthalmologic disordersincluding glaucoma, dry eye, or macular degeneration.

In some embodiments, the disorder is a free radical induced diseasestate.

In some embodiments, the disorder is acute or chronic pain. In oneembodiment, the pain is neuropathic pain.

Another embodiment disclosed herein is a method of hormonal replacementtherapy, comprising:

-   -   identifying a subject in need of hormonal replacement; and    -   administering to the subject a pharmaceutically effective amount        of a compound of formula I:

-   -   or a pharmaceutically acceptable salt or prodrug thereof,        wherein:    -   n is an integer selected from the group consisting of 3, 4, 5        and 6;    -   R₁ is selected from the group consisting of hydrogen, C₁-C₈        straight chained or branched alkyl, C₁-C₈ straight chained or        branched alkenyl, cycloalkyl, cycloalkenyl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroalicyclyl, sulphonyl, C₁-C₈        straight chained or branched perhaloalkyl, —C(═Z)R₆, —C(═Z)OR₆,        —C(═Z)N(R₆)₂, —S(═O)₂NR_(5a)R_(5b), —P(═O)(OR₆)₂, and        —CH₂OC(═O)R₅;    -   R₂, R_(2a), R_(2b), R_(2c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, halogen, sulfonyl, perhaloalkyl, —CN,        —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b), —NR₆N═CR_(6a)R_(6b),        —N(R₆)C(R_(6a))═NR_(6b), —C(═Z)R₆, —C(═Z)OR₆, —C(═Z)NR₆R_(6a),        —N(R₆)—C(═Z)R_(6a), —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆,        —N(R₆)—S(═O)₂R_(6a), and —SR₆;    -   each R₃ is separately selected from the group consisting of        hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted        or unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heteroalicyclyl, hydroxy, halogen,        sulfonyl, perhaloalkyl, —CN, ═O, and —OR₆, or are separately        absent to accommodate a double bond;    -   two R₃ groups are optionally bound together to form a        substituted or unsubstituted C₃-C₉ cycloalkyl or C₃-C₉        heteroalicyclyl;    -   R_(2a) is optionally bound to one R₃ group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   R_(4a) is optionally bound to one R₃ group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   any bond represented by a dashed and solid line represents a        bond selected from the group consisting of a single bond and a        double bond;    -   R₄, R_(4a), R_(4b), R_(4c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, nitro, halogen, sulfonyl,        perhaloalkyl, —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b),        —NR₆N═CR_(6a)R_(6b), —N(R₆)C(R_(6a))═NR_(6b), —CN, —C(═Z)R₆,        —C(═Z)OR₆, —C(═Z)NR₆R_(6a), —S(═Z)NR₆R_(6a), —N(R₆)—C(═Z)R_(6a),        —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆, —N(R₆)—S(═O)₂R_(6a), and        —SR₆;    -   R_(4a) and R_(4b) are optionally bound together to form an aryl,        heteroaryl, or heteroalicyclyl;    -   R₅ is selected from the group consisting of hydrogen, alkyl,        alkenyl, cycloalkyl, cycloalkenyl, halogen, —CN, —SR₆, sulfonyl,        —C(═O)NR₆R_(6a), —C(═O)R₆, —NR₆R_(6a), —COOR₆, and perhaloalkyl;    -   Z is oxygen or sulfur; and    -   R₆, R_(6a) and R_(6b) are separately selected from the group        consisting of hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted cycloalkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, and        substituted or unsubstituted heteroalicyclyl.

Another embodiment disclosed herein is a method of lowering cholesterol,triglycerides, or LDL levels, comprising:

-   -   identifying a subject in need of the lowering; and    -   administering to the subject a pharmaceutically effective amount        of a compound of formula I:

-   -   or a pharmaceutically acceptable salt or prodrug thereof,        wherein:    -   n is an integer selected from the group consisting of 3, 4, 5        and 6;    -   R₁ is selected from the group consisting of hydrogen, C₁-C₈        straight chained or branched alkyl, C₁-C8 straight chained or        branched alkenyl, cycloalkyl, cycloalkenyl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroalicyclyl, sulphonyl, C₁-C₈        straight chained or branched perhaloalkyl, —C(═Z)R₆, —C(═Z)OR₆,        —C(═Z)N(R₆)₂, —S(═O)₂NR_(5a)R_(5b), —P(═O)(OR₆)₂, and        —CH₂OC(═O)R₅;    -   R₂, R_(2a), R_(2b), R_(2c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, halogen, sulfonyl, perhaloalkyl, —CN,        —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b), —NR₆N═CR_(6a)R_(6b),        —N(R₆)C(R_(6a))═NR_(6b), —C(═Z)R₆, —C(═Z)OR₆, —C(═Z)NR₆R_(6a),        —N(R₆)—C(═Z)R_(6a), —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆,        —N(R₆)—S(═O)₂R_(6a), and —SR₆;    -   each R₃ is separately selected from the group consisting of        hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted        or unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heteroalicyclyl, hydroxy, halogen,        sulfonyl, perhaloalkyl, —CN, ═O, and —OR₆, or are separately        absent to accommodate a double bond;    -   two R₃ groups are optionally bound together to form a        substituted or unsubstituted C₃-C₉ cycloalkyl or C₃-C₉        heteroalicyclyl;    -   R_(2a) is optionally bound to one R₃ group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   R_(4a) is optionally bound to one R₃ group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   any bond represented by a dashed and solid line represents a        bond selected from the group consisting of a single bond and a        double bond;    -   R₄, R_(4a), R_(4b), R_(4c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, nitro, halogen, sulfonyl,        perhaloalkyl, —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b),        —NR₆N═CR_(6a)R_(6b), —N(R₆)C(R_(6a))═NR_(6b), —CN, —C(═Z)R₆,        —C(═Z)OR₆, —C(═Z)NR₆R_(6a), —S(═Z)NR₆R_(6a), —N(R₆)—C(═Z)R_(6a),        —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆, —N(R₆)—S(═O)₂R_(6a), and        —SR₆;    -   R_(4a) and R_(4b) are optionally bound together to form an aryl,        heteroaryl, or heteroalicyclyl;    -   R₅ is selected from the group consisting of hydrogen, alkyl,        alkenyl, cycloalkyl, cycloalkenyl, halogen, —CN, —SR₆, sulfonyl,        —C(═O)NR₆R_(6a), —C(═O)R₆, —NR₆R_(6a), —COOR₆, and perhaloalkyl;    -   Z is oxygen or sulfur; and    -   R₆, R_(6a) and R_(6b) are separately selected from the group        consisting of hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted cycloalkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, and        substituted or unsubstituted heteroalicyclyl.

Another embodiment disclosed herein is a method of treating impairedcognition or providing neuroprotection, comprising:

-   -   identifying a subject in need of the treating or        neuroprotection; and    -   administering to the subject a pharmaceutically effective amount        of a compound of formula I:

-   -   or a pharmaceutically acceptable salt or prodrug thereof,        wherein:    -   n is an integer selected from the group consisting of 3, 4, 5        and 6;    -   R₁ is selected from the group consisting of hydrogen, C₁-C₈        straight chained or branched alkyl, C₁-C₈ straight chained or        branched alkenyl, cycloalkyl, cycloalkenyl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroalicyclyl, sulphonyl, C₁-C₈        straight chained or branched perhaloalkyl, —C(═Z)R₆, —C(═Z)OR₆,        —C(═Z)N(R₆)₂, —S(═O)₂NR_(5a)R_(5b), —P(═O)(OR₆)₂, and        —CH₂OC(═O)R₅;    -   R₂, R_(2a), R_(2b), R_(2c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, halogen, sulfonyl, perhaloalkyl, —CN,        —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b), —NR₆N═CR_(6a)R_(6b),        —N(R₆)C(R_(6a))═NR_(6b), —C(═Z)R₆, —C(═Z)OR₆, —C(═Z)NR₆R_(6a),        —N(R₆)—C(═Z)R_(6a), —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆,        —N(R₆)—S(═O)₂R_(6a), and —SR₆;    -   each R₃ is separately selected from the group consisting of        hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted        or unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heteroalicyclyl, hydroxy, halogen,        sulfonyl, perhaloalkyl, —CN, ═O, and —OR₆, or are separately        absent to accommodate a double bond;    -   two R₃ groups are optionally bound together to form a        substituted or unsubstituted C₃-C₉ cycloalkyl or C₃-C₉        heteroalicyclyl;    -   R_(2a) is optionally bound to one R₃ group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   R_(4a) is optionally bound to one R₃ group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   any bond represented by a dashed and solid line represents a        bond selected from the group consisting of a single bond and a        double bond;    -   R₄, R_(4a), R_(4b), R_(4c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, nitro, halogen, sulfonyl,        perhaloalkyl, —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b),        —NR₆N═CR_(6a)R_(6b), —N(R₆)C(R_(6a))═NR_(6b), —CN, —C(═Z)R₆,        —C(═Z)OR₆, —C(═Z)NR₆R_(6a), —S(═Z)NR₆R_(6a), —N(R₆)—C(═Z)R_(6a),        —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆, —N(R₆)—S(═O)₂R_(6a), and        —SR₆;    -   R_(4a) and R_(4b) are optionally bound together to form an aryl,        heteroaryl, or heteroalicyclyl;    -   R₅ is selected from the group consisting of hydrogen, alkyl,        alkenyl, cycloalkyl, cycloalkenyl, halogen, —CN, —SR₆, sulfonyl,        —C(═O)NR₆R_(6a), —C(═O)R₆, NR₆R_(6a), —COOR₆, and perhaloalkyl;    -   Z is oxygen or sulfur; and    -   R₆, R_(6a) and R_(6b) are separately selected from the group        consisting of hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted cycloalkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, and        substituted or unsubstituted heteroalicyclyl.

Another embodiment disclosed herein is a method of preventingconception, comprising administering to a subject a pharmaceuticallyeffective amount of a compound of formula I:

-   -   or a pharmaceutically acceptable salt or prodrug thereof,        wherein:    -   n is an integer selected from the group consisting of 3, 4, 5        and 6;    -   R₁ is selected from the group consisting of hydrogen, C₁-C₈        straight chained or branched alkyl, C₁-C₈ straight chained or        branched alkenyl, cycloalkyl, cycloalkenyl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroalicyclyl, sulphonyl, C₁-C₈        straight chained or branched perhaloalkyl, —C(═Z)R₆, —C(═Z)OR₆,        —C(═Z)N(R₆)₂, —S(═O)₂NR_(5a)R_(5b), —P(═O)(OR₆)₂, and        —CH₂OC(═O)R₅;    -   R₂, R_(2a,) R_(2b), R_(2c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, halogen, sulfonyl, perhaloalkyl, —CN,        —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b), —NR₆N═CR_(6a)R_(6b),        —N(R₆)C(R_(6a))═NR_(6b), —C(═Z)R₆, —C(═Z)OR₆, —C(═Z)NR₆R_(6a),        —N(R₆)—C(═Z)R_(6a), —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆,        —N(R₆)—S(═O)₂R_(6a), and —SR₆;    -   each R₃ is separately selected from the group consisting of        hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted        or unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heteroalicyclyl, hydroxy, halogen,        sulfonyl, perhaloalkyl, —CN, ═O, and —OR₆, or are separately        absent to accommodate a double bond;    -   two R₃ groups are optionally bound together to form a        substituted or unsubstituted C₃-C₉ cycloalkyl or C₃-C₉        heteroalicyclyl;    -   R_(2a) is optionally bound to one R₃ group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   R_(4a) is optionally bound to one R₃ group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   any bond represented by a dashed and solid line represents a        bond selected from the group consisting of a single bond and a        double bond;    -   R₄, R_(4a), R_(4b, R) _(4c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, nitro, halogen, sulfonyl,        perhaloalkyl, —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b),        —NR₆N═CR_(6a)R_(6b), —N(R₆)C(R_(6a))═NR_(6b), —CN, —C(═Z)R₆,        —C(═Z)OR₆, —C(═Z)NR₆R_(6a), —S(═Z)NR₆R_(6a), —N(R₆)—C(═Z)R_(6a),        —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆, —N(R₆)—S(═O)₂R_(6a), and        —SR₆;    -   R_(4a) and R_(4b) are optionally bound together to form an aryl,        heteroaryl, or heteroalicyclyl;    -   R₅ is selected from the group consisting of hydrogen, alkyl,        alkenyl, cycloalkyl, cycloalkenyl, halogen, —CN, —SR₆, sulfonyl,        —C(═O)NR₆R_(6a), —C(═O)R₆, —NR₆R_(6a), —COOR₆, and perhaloalkyl;    -   Z is oxygen or sulfur; and    -   R₆, R_(6a) and R_(6b) are separately selected from the group        consisting of hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted cycloalkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, and        substituted or unsubstituted heteroalicyclyl.

Another embodiment disclosed herein is a method of modulating orspecifically agonizing one or more Estrogen receptors, comprising:

-   -   identifying a subject in need of the modulating or agonizing;        and    -   administering to the subject an effective amount of a compound        of formula I:

-   -   or a pharmaceutically acceptable salt or prodrug thereof,        wherein:    -   n is an integer selected from the group consisting of 3, 4, 5        and 6;    -   R₁ is selected from the group consisting of hydrogen, C₁-C₈        straight chained or branched alkyl, C₁-C₈ straight chained or        branched alkenyl, cycloalkyl, cycloalkenyl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroalicyclyl, sulphonyl, C₁-C₈        straight chained or branched perhaloalkyl, —C(═Z)R₆, —C(═Z)OR₆,        —C(═Z)N(R₆)₂, —S(═O)₂NR_(5a)R_(5b), —P(═O)(OR₆)₂, and        —CH₂OC(═O)R₅;    -   R₂, R_(2a), R_(2b), R_(2c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, halogen, sulfonyl, perhaloalkyl, —CN,        —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b), —NR₆N═CR_(6a)R_(6b),        —N(R₆)C(R_(6a))═NR_(6b), —C(═Z)R₆, —C(═Z)OR₆, —C(═Z)NR₆R_(6a),        —N(R₆)—C(═Z)R_(6a), —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆,        —N(R₆)—S(═O)₂R_(6a), and —SR₆;    -   each R₃ is separately selected from the group consisting of        hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted        or unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heteroalicyclyl, hydroxy, halogen,        sulfonyl, perhaloalkyl, —CN, ═O, and —OR₆, or are separately        absent to accommodate a double bond;    -   two R₃ groups are optionally bound together to form a        substituted or unsubstituted C₃-C₉ cycloalkyl or C₃-C₉        heteroalicyclyl;    -   R_(2a) is optionally bound to one R₃ group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   R_(4a) is optionally bound to one R₃ group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   any bond represented by a dashed and solid line represents a        bond selected from the group consisting of a single bond and a        double bond;    -   R₄, R_(4a), R_(4b), R_(4c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, nitro, halogen, sulfonyl,        perhaloalkyl, —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b),        —NR₆N═CR_(6a)R_(6b), —N(R₆)C(R_(6a))═NR_(6b), —CN, —C(═Z)R₆,        —C(═Z)OR₆, —C(═Z)NR₆R_(6a), —S(═Z)NR6R_(6a), —N(R₆)—C(═Z)R_(6a),        —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆, —N(R₆)—S(═O)₂R_(6a), and        —SR₆;    -   R_(4a) and R_(4b) are optionally bound together to form an aryl,        heteroaryl, or heteroalicyclyl;    -   R₅ is selected from the group consisting of hydrogen, alkyl,        alkenyl, cycloalkyl, cycloalkenyl, halogen, —CN, —SR₆, sulfonyl,        —C(═O)NR₆R_(6a), —C(═O)R₆, —NR₆R_(6a), —COOR₆, and perhaloalkyl;    -   Z is oxygen or sulfur; and    -   R₆, R_(6a) and R_(6b) are separately selected from the group        consisting of hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted cycloalkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, and        substituted or unsubstituted heteroalicyclyl.

In various embodiments of the methods described above, the compound isselected from the group consisting of:

In other embodiments of the methods described above, the compound is notselected from the group consisting of:

Another embodiment disclosed herein includes a compound of formula II:

-   -   or a pharmaceutically acceptable salt or prodrug thereof,        wherein:    -   n is an integer selected from the group consisting of 1, 2, 3,        4, 5 and 6;    -   R₁ is selected from the group consisting of hydrogen, C₁-C₈        straight chained or branched alkyl, C₁-C₈ straight chained or        branched alkenyl, cycloalkyl, cykloalkenyl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroalicyclyl, sulphonyl, C₁-C₈        straight chained or branched perhaloalkyl, —C(═Z)R₅, —C(═Z)OR₅,        —C(═Z)N(R₅)₂, —S(=O)₂NR_(5a)R_(5b), —P(═O)(OR₅)₂, and        —CH₂OC(═O)R₅;    -   R₂, R_(2a), R_(2b), R_(2c), and each R₆ are separately selected        from the group consisting of hydrogen, alkyl, alkenyl,        cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, substituted or        unsubstituted heteroalicyclyl, hydroxy, halogen, sulfonyl,        perhaloalkyl, —CN, —OR₅, —NR₅R_(5a), —NR₅NR_(5a)R_(5b),        —NR₅N═CR_(5a)R_(5b), —N(R₅)C(R_(5a))═NR_(5b), —C(═Z)R₅,        —C(═Z)OR₅, —C(═Z)NR₅R_(5a), —N(R₅)—C(═Z)R_(5a),        —N(R₅)—C(═Z)NR_(5b)R_(5a), —OC(═Z)R₅, —N(R₅)—S(═O)₂R_(5a), and        —SR₅;    -   each Y is separately selected from the group consisting of        methylene, methylene substituted with one or two R₆ groups,        sulphur, oxygen, unsubstituted nitrogen, nitrogen substituted        with R₅, and C═O;    -   two Y groups are optionally bound together to form a single bond        or a substituted or unsubstituted C₁-C₉ cycloalkyl or C₁-C₉        heteroalicyclyl;    -   R_(2a) is optionally bound to one Y group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   any bond represented by a dashed and solid line represents a        bond selected from the group consisting of a single bond and a        double bond;    -   A is selected from the group consisting of substituted        heteroaryl, unsubstituted heteroaryl, substituted        heteroalicyclyl, unsubstituted heteroalicyclyl, unsubstitued        aryl, and substituted aryl;    -   A is optionally bound to one Y group to form a substituted or        unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or C₄-C₉        cycloalkenyl;    -   Z is oxygen or sulfur; and    -   each R₅, R_(5a) and R_(5b) are separately selected from the        group consisting of hydrogen, substituted or unsubstituted        alkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted cycloalkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, and        substituted or unsubstituted heteroalicyclyl;    -   provided that when every Y is a substituted or unsubstituted        methylene, then A is not a substituted or unsubstituted aryl.

In some embodiments, when A is a substituted aryl, it is not substitutedat the para position.

In some embodiments of the compound of formula II, n is an integerselected from the group consisting of 3, 4, and 5; R₁ is selected fromthe group consisting of hydrogen, C₁-C₄ straight chained or branchedalkyl, C₁-C₄ straight chained or branched alkenyl, C₁-C₄ straightchained or branched perhaloalkyl, and substituted or unsubstituted aryl;R₂, R_(2a), R_(2b), R_(2c) are separately selected from the groupconsisting of hydrogen, C₁-C₅ straight chained or branched alkyl, C₁-C₅alkenyl, hydroxy, halogen, sulfonyl, perhaloalkyl, —CN, —OR₅, —C(═O)R₅,—C(═O)OR₅, —C(═O)NR₅R_(5a), —N(R₅)—C(═O)R_(5a), —N(R₅)—S(═O)₂R_(5a),—OC(═O)R₅, and —SR₅; each Y is separately selected from the groupconsisting of substituted or unsubstituted methylene, sulphur, oxygen,substituted or unsubstituted nitrogen or C═O; and A is selected from thegroup consisting of substituted heteroaryl, unsubstituted heteroaryl,unsubstitued aryl, and substituted aryl that is unsubstituted at thepara position.

In some embodiments of the compound of formula II, n is 3; R₁ isselected from the group consisting of hydrogen, C₁-C₅ straight chainedor branched alkyl, substituted or unsubstituted aryl; R₂, R_(2a),R_(2b), R_(2c) are separately selected from the group consisting ofhydrogen, C₁-C₅ straight chained or branched alkyl, F, Cl, Br,perhaloalkyl, —CN, —OR₅, —C(═O), and —SR₅; each Y is separately selectedfrom the group consisting of substituted or unsubstituted methylene,oxygen, substituted or unsubstituted nitrogen, or C═O; and A is selectedfrom the group consisting of substituted heteroaryl, unsubstitutedheteroaryl, unsubstitued aryl, and substituted aryl that isunsubstituted at the para position.

In some embodiments, the compound of formula II is selected from thegroup consisting of:

or a pharmaceutically acceptable salt or prodrug thereof.

Another embodiment disclosed herein includes a method of treating orpreventing disorders selected from the group consisting of inflammatorybowel syndrome; Crohn's disease; ulcerative proctitis or colitis;prostatic hypertrophy; uterine leiomyomnas; breast carcinoma;endometrial carcinoma; polycystic ovary syndrome; endometrial polyps;benign breast disease; adenomyosis; ovarian carcinoma; melanoma;prostate carcinoma; colon carcinoma; brain tumors includingglioblastoma, astrocytoma, glioma, or meningioma; prostatitis;interstitial cystitis; bone density loss including osteoporosis orosteopenia; discholesterolemia; dislipidemia; cardiovascular disease;atherosclerosis; hypertension; peripheral vascular disease; restenosis;vasospasm; neurodegenerative disorders including Alzheimer's disease,Huntington's disease, Parkinson's disease or other dementias; spinalcord injuries; cognitive decline; stroke; anxiety; vaginal atrophy;vulvar atrophy; atrophic vaginitis; vaginal dryness; pruritus;dyspareunia; frequent urination; urinary incontinence; urinary tractinfections; vasomotor symptoms including flusing or hot flashes;arthritis including rheumatoid arthritis, osteoarthritis, orarthropathiesendometriosis; psoriasis; dermatitis; asthma; pleurisy;multiple sclerosis; systemic lupus erthematosis; uveitis; sepsis;hemmorhagic shock; type II diabetes; acute or chronic inflammation;acute or chronic pain; lung disorders including asthma or chronicobstructive pulmonary disease; ophthalmologic disorders includingglaucoma, dry eye, or macular degeneration; and free radical induceddisease states; comprising:

-   -   identifying a subject in need of the treating or preventing; and    -   administering to the subject a pharmaceutically effective amount        of a compound of formula II, or a pharmaceutically acceptable        salt or prodrug thereof.

In some embodiments, the disorder is selected from the group consistingof inflammatory bowel syndrome, Crohn's disease, and ulcerativeproctitis or colitis.

In some embodiments, the disorder is selected from the group consistingof prostatic hypertrophy, uterine leiomyomnas, breast carcinoma,endometrial carcinoma, polycystic ovary syndrome, endometrial polyps,benign breast disease, adenomyosis, ovarian carcinoma, melanoma,prostate carcinoma, colon carcinoma, and brain tumors includingglioblastoma, astrocytoma, glioma, or meningioma.

In some embodiments, the disorder is selected from the group consistingof prostatitis and interstitial cystitis.

In some embodiments, the disorder is bone density loss includingosteoporosis and osteopenia.

In some embodiments, the disorder is selected from the group consistingof discholesterolemia and dislipidemia.

In some embodiments, the disorder is selected from the group consistingof cardiovascular disease, atherosclerosis, hypertension, peripheralvascular disease, restenosis and vasospasm.

In some embodiments, the disorder is a neurodegenerative disorderincluding Alzheimer's disease, Huntington's disease, Parkinson's diseaseor other dementia.

In one embodiment, the disorder is a spinal cord injury.

In some embodiments, the disorder is selected from the group consistingof cognitive decline, stroke, and anxiety.

In some embodiments, the disorder is selected from the group consistingof vaginal atrophy, vulvar atrophy, atrophic vaginitis, vaginal dryness,pruritus, dyspareunia, frequent urination, urinary incontinence, andurinary tract infections.

In some embodiments, the disorder is one or more vasomotor symptomsincluding flushing or hot flashes.

In some embodiments, the disorder is endometriosis.

In some embodiments, the disorder is arthritis including rheumatoidarthritis, osteoarthritis, or arthropathies.

In some embodiments, the disorder is selected from the group consistingof psoriasis and dermatitis.

In some embodiments, the disorder is selected from the group consistingof asthma and pleurisy.

In some embodiments, the disorder is selected from the group consistingof multiple sclerosis, systemic lupus erthematosis, uveitis, sepsis, andhemmorhagic shock.

In some embodiments, the disorder is type II diabetes.

In some embodiments, the disorder is selected from the group consistingof acute and chronic inflammation.

In some embodiments, the disorder is a lung disorders including asthmaor chronic obstructive pulmonary disease.

In some embodiments, the disorder is an ophthalmologic disordersincluding glaucoma, dry eye, or macular degeneration.

In some embodiments, the disorder is a free radical induced diseasestate.

In some embodiments, the disorder is acute or chronic pain. In oneembodiment, the pain is neuropathic pain.

Another embodiment disclosed herein includes a method of hormonalreplacement therapy, including identifying a subject in need of hormonalreplacement and administering to the subject a pharmaceuticallyeffective amount of a compound of formula II, or a pharmaceuticallyacceptable salt or prodrug thereof.

Another embodiment disclosed herein includes a method of loweringcholesterol, triglycerides, or LDL levels, including identifying asubject in need of the lowering and administering to the subject apharmaceutically effective amount of a compound of formula II, or apharmaceutically acceptable salt or prodrug thereof.

Another embodiment disclosed herein includes a method of treatingimpaired cognition or providing neuroprotection, including identifying asubject in need of the treating or neuroprotection and administering tothe subject a pharmaceutically effective amount of a compound of formulaII, or a pharmaceutically acceptable salt or prodrug thereof.

Another embodiment disclosed herein includes a method of preventingconception, including administering to a subject a pharmaceuticallyeffective amount of a compound of formula II, or a pharmaceuticallyacceptable salt or prodrug thereof.

Another embodiment disclosed herein includes a method of modulating orspecifically agonizing one or more Estrogen receptors, includingidentifying a subject in need of the modulating or agonizing andadministering to the subject an effective amount of a compound offormula II, or a pharmaceutically acceptable salt or prodrug thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts agonist activity of ERB-002 at the estrogen receptors asevaluated using the Receptor and Selection Amplification (R-SAT)technology.

FIG. 2 is a graph depicting rat paw hot plate latency illustrating thereversal of thermal hyperalgesia by ERB-002.

FIG. 3 is a graph depicting rat paw thickness illustrating the reversalof edema by ERB-002.

FIG. 4 is a bar graph depicting uterine weight illustrating that ERB-002does not display uterotrophic properties in vivo in immature femalerats.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

In various embodiments, compounds having the formula (I) and methods forusing these compounds for treating disorders related to estrogenreceptors are provided:

In some embodiments, pharmaceutically acceptable salt or prodrugs of thecompound of formula I are provided. In the compound of formula I:

-   -   n is an integer selected from the group consisting of 3, 4, 5        and 6;    -   R₁ is selected from the group consisting of hydrogen, C₁-C₈        straight chained or branched alkyl, C₁-C₈ straight chained or        branched alkenyl, cycloalkyl, cycloalkenyl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroalicyclyl, sulphonyl, C₁-C₈        straight chained or branched perhaloalkyl, —C(═Z)R₆, —C(═Z)OR₆,        —C(═Z)N(R₆)₂, —S(═O)₂NR_(5a)R_(5b), —P(═O)(OR₆)₂, and        —CH₂OC(═O)R₅;    -   R₂, R_(2a), R_(2b), R_(2c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, halogen, sulfonyl, perhaloalkyl, —CN,        —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b), —NR₆N═CR_(6a)R_(6b),        —N(R₆)C(R_(6a))═NR_(6b), —C(═Z)R₆, —C(═Z)OR₆, —C(═Z)NR₆R_(6a),        —N(R₆)—C(═Z)R_(6a), —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆,        —N(R₆)—S(═O)₂R_(6a), and SR₆;    -   each R₃ is separately selected from the group consisting of        hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted        or unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heteroalicyclyl, hydroxy, halogen,        sulfonyl, perhaloalkyl, —CN, ═O, and —OR₆, or are separately        absent to accommodate a double bond;    -   two R₃ groups are optionally bound together to form a        substituted or unsubstituted C₃-C₉ cycloalkyl or C₃-C₉        heteroalicyclyl;    -   R_(2a) is optionally bound to one R₃ group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   R_(4a) is optionally bound to one R₃ group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   any bond represented by a dashed and solid line represents a        bond selected from the group consisting of a single bond and a        double bond;    -   R₄, R_(4a), R_(4b), R_(4c) are separately selected from the        group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroalicyclyl, hydroxy, nitro, halogen, sulfonyl,        perhaloalkyl, —OR₆, —NR₆R_(6a), —NR₆NR_(6a)R_(6b),        —NR₆N═CR_(6a)R_(6b), —N(R₆)C(R_(6a))═NR_(6b), —CN, —C(═Z)R₆,        —C(═Z)OR₆, —C(═Z)NR₆R_(6a), —S(═Z)NR₆R_(6a), —N(R₆)—C(═Z)R_(6a),        —N(R₆)—C(═Z)NR_(6b)R_(6a), —OC(═Z)R₆, —N(R₆)—S(═O)₂R_(6a), and        —SR₆;    -   R_(4a) and R_(4b) are optionally bound together to form an aryl,        heteroaryl, or heteroalicyclyl;    -   R₅ is selected from the group consisting of hydrogen, alkyl,        alkenyl, cycloalkyl, cycloalkenyl, halogen, —CN, —SR₆, sulfonyl,        —C(═O)NR₆R_(6a), —C(═O)R₆, —NR₆R_(6a), —COOR₆, and perhaloalkyl;    -   Z is oxygen or sulfur; and    -   R₆, R_(6a) and R_(6b) are separately selected from the group        consisting of hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted cycloalkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, and        substituted or unsubstituted heteroalicyclyl.

In some embodiments, compounds are provided according to formula I butexcluding the compounds selected from the group consisting of:

In some embodiments of the compound of formula I:

-   -   n is an integer selected from the group consisting of 3, 4, and        5;    -   R₁ is selected from the group consisting of hydrogen, C₁-C₄        straight chained or branched alkyl, C₁-C₄ straight chained or        branched alkenyl, C₁-C₄ straight chained or branched        perhaloalkyl, and substituted or unsubstituted aryl;    -   R₂, R_(2a), R_(2b), R_(2c) are separately selected from the        group consisting of hydrogen, C₁-C₅ straight chained or branched        alkyl, C₁-C₅ alkenyl, hydroxy, halogen, sulfonyl, perhaloalkyl,        —CN, —OR₆, —C(═O)R₆, —C(═O)OR₆, —C(═O)NR₆R_(6a),        —N(R₆)—C(═O)R_(6a), —N(R₆)—S(═O)₂R_(6a), —OC(═O)R₆, and —SR₆;    -   each R₃ is separately selected from the group consisting of        hydrogen, C₁-C₅ straight chained or branched alkyl, C₁-C₅        alkenyl, cycloalkyl, cycloalkenyl, hydroxy, halogen, sulfonyl,        perhaloalkyl, —CN, ═O, and —OR₆, or each R₃ is separately absent        to accommodate a double bond;    -   R₄, R_(4a), R_(4b), R_(4c) are separately selected from the        group consisting hydrogen, C₁-C₅ straight chained or branched        alkyl, C₁-C₅ alkenyl, hydroxy, halogen, sulfonyl, perhaloalkyl,        —OR₆, —CN, —C(═O)R₆, —C(═O)OR₆, —C(═O)NR₆R_(6a),        —S(═O)₂NR₆R_(6a), —N(R₆)—C(═O)R_(6a), —OC(═Z)R₆,        —N(R₆)—S(═O)₂R_(6a), and —SR₆; and    -   R₅ is selected from the group consisting of hydrogen, C₁-C₅        straight chained or branched alkyl, halogen, —CN, —SR₆,        sulfonyl, —OCF₃, and perhaloalkyl.

In other embodiments of the compound of formula I:

-   -   n is 3;    -   R₁ is selected from the group consisting of hydrogen, C₁-C₅        straight chained or branched alkyl, substituted or unsubstituted        aryl;    -   R₂, R_(2a), R_(2b), R_(2c) are separately selected from the        group consisting of hydrogen, C₁-C₅ straight chained or branched        alkyl, F, Cl, Br, perhaloalkyl, —CN, —OR₆, —C(═O), and —SR₆;    -   each R₃ is separately selected from the group consisting of        hydrogen, C₁-C₅ straight chained or branched alkyl, C₁-C₅        alkenyl, cycloalkyl, halogen, perhaloalkyl, —CN, and —OR₆, or        each R₃ is separately absent to accommodate a double bond;    -   each R₄, R_(4a), R_(4b), R_(4c) is separately selected from the        group consisting hydrogen, C₁-C₅ straight chained or branched        alkyl, halogen, sulfonyl, perhaloalkyl, —OR₆, —CN,        —N(R₆)—S(═O)₂R_(6a), and —SR₆; and    -   R₅ is selected from the group consisting of hydrogen, C₁-C₅        straight chained or branched alkyl, F, Cl, —CN, —SR₆, —OCF₃, and        CF₃.

In some embodiments, the compound of formula I is selected from thegroup consisting of:

In various other embodiments, compounds having the formula (II) andmethods for using these compounds for treating disorders related toestrogen receptors are provided:

In some embodiments, pharmaceutically acceptable salts or prodrugs ofthe compound of formula II are provided. In the compound of formula II:

-   -   n is an integer selected from the group consisting of 1, 2, 3,        4, 5 and 6;    -   R₁ is selected from the group consisting of hydrogen, C₁-C₈        straight chained or branched alkyl, C₁-C₈ straight chained or        branched alkenyl, cycloalkyl, cykloalkenyl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroalicyclyl, sulphonyl, C₁-C₈        straight chained or branched perhaloalkyl, —C(═Z)R₅, —C(═Z)OR₅,        —C(═Z)N(R₅)₂, —S(═O)₂NR_(5a)R_(5b), —P(═O)(OR₅)₂, and        —CH₂OC(═O)R₅;    -   R₂, R_(2a), R_(2b), R_(2c), and each R₆ are separately selected        from the group consisting of hydrogen, alkyl, alkenyl,        cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, substituted or        unsubstituted heteroalicyclyl, hydroxy, halogen, sulfonyl,        perhaloalkyl, —CN, —OR₅, —NR₅R_(5a), —NR₅NR_(5a)R_(5b),        —NR₅N═CR_(5a)R_(5b), —N(R₅)C(R_(5a))═NR_(5b), —C(═Z)R₅,        —C(═Z)OR₅, —C(═Z)NR₅R_(5a), —N(R₅)—C(═Z)R_(5a),        —N(R₅)—C(═Z)NR_(5b)R_(5a), —OC(═Z)R₅, —N(R₅)—S(═O)₂R_(5a), and        —SR₅;    -   each Y is separately selected from the group consisting of        methylene, methylene substituted with one or two R₆ groups,        sulphur, oxygen, unsubstituted nitrogen, nitrogen substituted        with R₅, and C═O;    -   two Y groups are optionally bound together to form a single bond        or a substituted or unsubstituted C₁-C₉ cycloalkyl or C₁-C₉        heteroalicyclyl;    -   R_(2a) is optionally bound to one Y group to form a substituted        or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or        C₄-C₉ cycloalkenyl;    -   any bond represented by a dashed and solid line represents a        bond selected from the group consisting of a single bond and a        double bond;    -   A is selected from the group consisting of substituted        heteroaryl, unsubstituted heteroaryl, substituted        heteroalicyclyl, unsubstituted heteroalicyclyl, unsubstitued        aryl, and substituted aryl;    -   A is optionally bound to one Y group to form a substituted or        unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or C₄-C₉        cycloalkenyl;    -   Z is oxygen or sulfur; and    -   each R₅, R_(5a) and R_(5b) are separately selected from the        group consisting of hydrogen, substituted or unsubstituted        alkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted cycloalkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, and        substituted or unsubstituted heteroalicyclyl;    -   provided that when every Y is a substituted or unsubstituted        methylene, then A is not a substituted or unsubstituted aryl.

In some embodiments, when A is a substituted aryl, it is not substitutedat the para position.

In one embodiment of the compound of formula II, n is an integerselected from the group consisting of 3, 4, and 5; R₁ is selected fromthe group consisting of hydrogen, C₁-C₄ straight chained or branchedalkyl, C₁-C₄ straight chained or branched alkenyl, C₁-C₄ straightchained or branched perhaloalkyl, and substituted or unsubstituted aryl;R₂, R_(2a), R_(2b), R_(2c) are separately selected from the groupconsisting of hydrogen, C₁-C₅ straight chained or branched alkyl, C₁-C₅alkenyl, hydroxy, halogen, sulfonyl, perhaloalkyl, —CN, —OR₅, —C(═O)R₅,—C(═O)OR₅, —C(═O)NR₅R_(5a), —N(R₅)—C(═O)R_(5a), N(R₅)—S(═O)₂R_(5a),—OC(═O)R₅, and —SR₅; each Y is separately selected from the groupconsisting of substituted or unsubstituted methylene, sulphur, oxygen,substituted or unsubstituted nitrogen or C═O; and A is selected from thegroup consisting of substituted heteroaryl, unsubstituted heteroaryl,unsubstitued aryl, and substituted aryl that is unsubstituted at thepara position.

In another embodiment of the compound of formula II, n is 3; R₁ isselected from the group consisting of hydrogen, C₁-C₅ straight chainedor branched alkyl, substituted or unsubstituted aryl; R₂, R_(2a),R_(2b), R_(2c) are separately selected from the group consisting ofhydrogen, C₁-C₅ straight chained or branched alkyl, F, Cl, Br,perhaloalkyl, —CN, —OR₅, —C(═O), and —SR₅; each Y is separately selectedfrom the group consisting of substituted or unsubstituted methylene,oxygen, substituted or unsubstituted nitrogen, or C═O; and A is selectedfrom the group consisting of substituted heteroaryl, unsubstitutedheteroaryl, unsubstitued aryl, and substituted aryl that isunsubstituted at the para position.

In various embodiments, the compound of formula II is selected from thegroup consisting of:

or a pharmaceutically acceptable salt or prodrug thereof.

DEFINITIONS

Unless otherwise specified, “R” group(s) such as, without limitation, R,R^(a) and R^(b), is(are) independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl (bonded to the indicated group at a ring carbon atom) andheteroalicyclyl (likewise bonded to the indicated group at a ring carbonatom), as these groups are defined herein. If two “R” groups arecovalently bonded to the same atom then they may be bound together so asto form a cycloalkyl or heteroalicyclyl group.

Unless otherwise indicated, when a substituent is deemed to be“optionally substituted,” it is meant that the substituent is a groupthat may be substituted with one or more group(s) individually andindependently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxyl, alkoxy, aryloxy, mercapto,alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato,thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, andamino, including mono- and di-substituted amino groups, and theprotected derivatives thereof. The protecting groups that may form theprotective derivatives of the above substituents are known to those ofskill in the art and may be found in references such as Greene and Wuts,Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wiley & Sons,New York, N.Y., 1999, which is incorporated herein in its entirety.

As used herein, “C_(m) to C_(n)” in which “m” and “n” are integersrefers to the number of carbon atoms in an alkyl, alkenyl or alkynylgroup or the number of carbon atoms in the ring of a cycloalkyl orcycloalkenyl group. That is, the alkyl, alkenyl, alkynyl, ring of thecycloalkyl or ring of the cycloalkenyl can contain from “m” to “n”,inclusive, carbon atoms. Thus, for example, a “C₁ to C₄ alkyl” grouprefers to all alkyl groups having from 1 to 4 carbons, that is, CH₃—,CH₃CH₂—, CH₃CH₂CH₂—, CH₃CH(CH₃)—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)—, and(CH₃)₃CH—. If no “m” and “n” are designated with regard to an alkyl,alkenyl, alkynyl, cycloalkyl or cycloalkenyl group, the broadest rangedescribed in these definitions is to be assumed.

As used herein, “aryl” refers to a carbocyclic (all carbon) ring or twoor more fused rings (rings that share two adjacent carbon atoms) thathave a fully delocalized pi-electron system. Examples of aryl groupsinclude, but are not limited to, benzene, naphthalene and azulene.

As used herein, “heteroaryl” refers to a ring or two or more fused ringsthat contain(s) one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur in the ring and that have afully delocalized pi-electron system. Examples of heteroaryl ringsinclude, but are not limited to, furan, thiophene, phthalazinone,pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole,triazole, thiadiazole, pyran, pyridine, pyridazine, pyrimidine, pyrazineand triazine.

As used herein, “alkyl” refers to a straight or branched chain fullysaturated (no double or triple bonds) hydrocarbon group. An alkyl groupof this invention may comprise from 1 to 20 carbon atoms, that is, m=1and n=20. An alkyl group herein may also be of medium size having 1 to10 carbon atoms. An alkyl group herein may also be a lower alkyl having1 to 5 carbon atoms. Examples of alkyl groups include, withoutlimitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, amyl, tert-amyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl and dodecyl.

An alkyl group of this invention may be substituted or unsubstituted.When substituted, the substituent group(s) is(are) one or more group(s)independently selected from cycloalkyl, aryl, heteroaryl,heteroalicyclyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, mercapto,alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, silyl,trihalomethanesulfonyl, —NR^(a)R^(b) and protected amino.

As used herein, “alkenyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more double bonds. Analkenyl group of this invention may be unsubstituted or substituted.When substituted, the substituent(s) may be selected from the samegroups disclosed above with regard to alkyl group substitution.

As used herein, “alkynyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more triple bonds. Analkynyl group of this invention may be unsubstituted or substituted.When substituted, the substituent(s) may be selected from the samegroups disclosed above with regard to alkyl group substitution.

As used herein, “acyl” refers to an “RC(═O)—” group with R as definedabove.

As used herein, “cycloalkyl” refers to a completely saturated (no doublebonds) hydrocarbon ring. Cycloalkyl groups of this invention may rangefrom C₃ to C₈. A cycloalkyl group may be unsubstituted or substituted.If substituted, the substituent(s) may be selected from those indicatedabove with regard to substitution of an alkyl group.

As used herein, “cycloalkenyl” refers to a cycloalkyl group thatcontains one or more double bonds in the ring although, if there is morethan one, they cannot form a fully delocalized pi-electron system in thering (otherwise the group would be “aryl,” as defined herein). Acycloalkenyl group of this invention may unsubstituted or substituted.When substituted, the substituent(s) may be selected from the samegroups disclosed above with regard to alkyl group substitution.

The term “alkylene” refers to an alkyl group, as defined here, which isa biradical and is connected to two other moieties. Thus, methylene(—CH₂—), ethylene (—CH₂CH₂—), proylene (—CH₂CH₂CH₂—), isopropylene(—CH₂—CH(CH₃)—), and isobutylene (—CH₂—CH(CH₃)—CH₂—) are examples,without limitation, of an alkylene group. Similar, theterm“cycloalkylene” refers to an cycloalkyl group, as defined here,which binds in an analogues way to two other moieties. If the alkyl andcycloalkyl groups contains unsaturated carbons, the terms “alkenylene”and “cycloalkenylene” are used.

As used herein, “heteroalicyclic” or heteroalicyclyl” refers to a ringor one or more fused rings having in the ring system one or moreheteroatoms independently selected from nitrogen, oxygen and sulfur. Therings may also contain one or more double bonds provided that they donot form a fully delocalized pi-electron system in the rings.Heteroalicyclyl groups of this invention may be unsubstituted orsubstituted. When substituted, the substituent(s) may be one or moregroups independently selected from the group consisting of halogen,hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy,carboxy, protected carboxy, amino, protected amino, carboxamide,protected carboxamide, alkylsulfonamido and trifluoromethanesulfonamido.

An “O-carboxy” group refers to a “RC(═O)O—” group with R as definedabove.

A “C-carboxy” group refers to a “—C(═O)R” group with R as defined above.

An “acetyl” group refers to a CH₃C(═O)— group.

A “trihalomethanesulfonyl” group refers to an “X₃CSO₂—” group wherein Xis a halogen.

A “cyano” group refers to a “—CN” group.

An “isocyanato” group refers to an “—NCO” group.

A “thiocyanato” group refers to a “—CNS” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “sulfinyl” group refers to an “—S(═O)—R” group with R as definedabove.

A “sulfonyl” group refers to an “SO₂R” group with R as defined above.

An “S-sulfonamido” group refers to a “—SO₂NR^(a)R^(b)” group with R^(a)and R^(b) as defined above.

An “N-sulfonamido” group refers to a “RSO₂N(R^(a))—” group with R andR^(a) as defined above.

A “trihalomethanesulfonamido” group refers to an “X₃CSO₂N(R)—” groupwith X as halogen and R as defined above.

An “O-carbamyl” group refers to a “—OC(═O)NR^(a)R^(b)” group with R^(a)and R^(b) as defined above.

An “N-carbamyl” group refers to an “ROC(═O)NR^(a)—” group with R^(a) andR as defined above.

An “O-thiocarbamyl” group refers to a “—OC(═S)—NR^(a)R^(b)” group withR^(a) and R^(b) as defined above.

An “N-thiocarbamyl” group refers to an “ROC(═S)NR^(a)—” group with R^(a)and R as defined above.

A “C-amido” group refers to a “—C(═O)NR^(a)R^(b)” group with R^(a) andR^(b) as defined above.

An “N-amido” group refers to a “RC(═O)NR^(a)—” group with R and R^(a) asdefined above.

The term “perhaloalkyl” refers to an alkyl group in which all thehydrogen atoms are replaced by halogen atoms.

As used herein, an “ester” refers to a “—C(═O)OR” group with R asdefined above.

As used herein, an “amide” refers to a “—C(═O)NR^(a)R^(b)” group withR^(a) and R^(b) as defined above.

Any unsubstituted or monosubstituted amine group on a compound hereincan be converted to an amide, any hydroxyl group can be converted to anester and any carboxyl group can be converted to either an amide orester using techniques well-known to those skilled in the art (see, forexample, Greene and Wuts, Protective Groups in Organic Synthesis, 3^(rd)Ed., John Wiley & Sons, New York, N.Y., 1999).

When two substituents are referred to herein as optionally bindingtogether, it is meant that the groups may be joined to form acycloalkyl, aryl, heteroaryl, or heteroalicyclyl group. For example,without limitation, if R^(a) and R^(b) of an NR^(a)R^(b) group areindicated to be optionally bound together, it is meant that they arecovalently bonded to one another at their terminal atoms to form a ring:

It is understood that, in any compound of this invention having one ormore chiral centers, if an absolute stereochemistry is not expresselyindicated, then each center may independently be R or S or a mixturethereof. In addition it is understood that, in any compound of thisinvention having one or more double bond(s) generating geometricalisomers that can be defined as E or Z each double bond may independentlybe E or Z a mixture thereof.

As used herein, “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to a patient towhich it is administered and does not abrogate the biological activityand properties of the compound. Pharmaceutical salts can be obtained byreaction of a compound disclosed herein with an acid or base.Base-formed salts include, without limitation, ammonium salt (NH₄ ⁺);alkali metal, such as, without limitation, sodium or potassium, salts;alkaline earth, such as, without limitation, calcium or magnesium,salts; salts of organic bases such as, without limitation,dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine;and salts with the amino group of amino acids such as, withoutlimitation, arginine and lysine. Useful acid-based salts include,without limitation, hydrochlorides, hydrobromides, sulfates, nitrates,phosphates, methanesulfonates, ethanesulfonates, p-toluenesulfonates andsalicylates.

A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may decrease the rate of metabolic degradation for instance bydecreasing O-glucuronidation and or O-sulfation. The prodrug may alsohave improved solubility in pharmaceutical compositions over the parentdrug. An example, without limitation, of a prodrug would be a compounddisclosed herein, which is administered as an ester (the “prodrug”) tofacilitate absorption over a cell membrane where water solubility isdetrimental to mobility but which then is metabolically hydrolyzed tothe carboxylic acid, the active entity, once inside the cell wherewater-solubility is beneficial. A further example of a prodrug might bea short peptide (polyaminoacid) bonded to an acid group where thepeptide is metabolized to reveal the active moiety.

Synthesis

General synthetic routes to the compounds of this invention are shown inSchemes 1-5. The routes shown are illustrative only and are notintended, nor are they to be construed, to limit the scope of thisinvention in any manner whatsoever. Those skilled in the art will beable to recognize modifications of the disclosed synthesis and to devisealternate routes based on the disclosures herein; all such modificationsand alternate routes are within the scope of this invention.

Synthetic rounts for synthesizing the compounds of formula I include thefollowing Schemes 1-6:

In the above schemes, it is to be understood that the moiety:

is identical to the moiety:

as described above with respect to Formula I.

Synthetic rounts for synthesizing the compounds of formula II includethe following Schemes 7-17:

Also disclosed herein are methods of treating clinical manifestations inwhich estrogen receptor function is altered; a method of treating orpreventing inflammatory bowel syndrome, Crohn's disease, ulcerativeproctitis or colitis; a method of treating or preventing prostatichypertrophy, uterine leiomyomnas, breast carcinoma, endometrialcarcinoma, polycystic ovary syndrome, endometrial polyps, benign breastdisease, adenomyosis, ovarian carcinoma, melanoma, prostate carcinoma,colon carcinoma, or brain tumors including glioblastoma, astrocytoma,glioma, or meningioma; a method of treating or preventing prostatitis orinterstitial cystitisl; a method of hormonal replacement therapy; amethod of treating or preventing bone density loss includingosteoporosis and osteopenia; a method of lowering cholesterol,triglycerides, or LDL levels; a method of treating or preventingdischolesterolemia or dislipidemia; a method of treating or preventingcardiovascular disease, atherosclerosis, hypertension, peripheralvascular disease, restenosis or vasospasm; a method of treating impairedcognition or providing neuroprotection; a method of treating orpreventing neurodegenerative disorders, including Alzheimer's disease,Huntington's disease, Parkinson's disease or other dementias; a methodof treating a spinal cord injury; a method of treating or preventingcognitive decline, stroke, or anxiety; a method of treating orpreventing free radical induced disease states; a method of treating orpreventing vaginal atrophy, vulvar atrophy, atrophic vaginitis, vaginaldryness, pruritus, dyspareunia, frequent urination, urinaryincontinence, or urinary tract infections; a method of treating orpreventing vasomotor symptoms including flushing or hot flashes; amethod of preventing conception; a method of treating or preventingendometriosis; a method of treating or preventing arthritis, includingbut not limited to rheumatoid arthritis, osteoarthritis, orarthropathies; a method of treating or preventing psoriasis ordermatitis, a method of treating or preventing asthma or pleurisy; amethod of treating or preventing multiple sclerosis, systemic lupuserthematosis, uveitis, sepsis, or hemmorhagic shock; a method oftreating or preventing type II diabetes; a method for treating acute andchronic inflammation of any type; a method of treating or preventinglung disorders such as asthma, chronic obstructive pulmonary disease; amethod of treating or preventing acute or chronic pain, includingneuropathic pain; a method of treating or preventing ophthalmologicdisorders including but not limited to glaucoma, dry eye, maculardegeneration, and a method of modulating or specifically agonizing oneor more Estrogen receptors where the methods comprise identifying asubject in need of treatment or prevention and administering to thesubject a pharmaceutically effective amount of a compound of formula Ior II.

Another embodiment is a method of identifying a compound that alleviatesinflammation in a subject, comprising identifying a subject sufferingfrom inflammation; providing the subject with at least one compound ofFormula I or II, as defined herein; and determining if the at least onecompound reduces inflammation in the subject.

The term “subject” refers to an animal, preferably a mammal, and mostpreferably a human, who is the object of treatment, observation orexperiment. The mammal may be selected from the group consisting ofmice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows,primates, such as monkeys, chimpanzees, and apes, and humans.

The term “therapeutically effective amount” is used to indicate anamount of an active compound, or pharmaceutical agent, that elicits thebiological or medicinal response indicated. This response may occur in atissue, system, animal or human that is being sought by a researcher,veterinarian, medical doctor or other clinician, and includesalleviation of the symptoms of the disease being treated.

Another embodiment is a method of identifying a compound which regulatesactivity of an Estrogen receptor by culturing cells that express theEstrogen receptors; incubating the cells with at least one compound ofFormula I or II as defined herein; and determining any change inactivity of the Estrogen receptors so as to identify a compound ofFormula I or II which regulates activity of a Estrogen receptors.

In other embodiments, methods are provided for alleviating diseases byadministering one or more compounds of Formula I or II. These methodsinclude, but are not limited to methods such as: a method of treatingclinical manifestations in which estrogen receptor function is altered;a method of treating or preventing inflammatory bowel syndrome, Crohn'sdisease, ulcerative proctitis or colitis; a method of treating orpreventing prostatic hypertrophy, uterine leiomyomnas, breast carcinoma,endometrial carcinoma, polycystic ovary syndrome, endometrial polyps,benign breast disease, adenomyosis, ovarian carcinoma, melanoma,prostate carcinoma, colon carcinoma, brain tumors including but notlimited to glioblastoma, astrocytoma, glioma, and meningioma; a methodof treating or preventing prostatitis or interstitial cystitis; a methodof hormonal replacement therapy; a method of treating or preventing bonedensity loss including but not limited to osteoporosis or osteopenia; amethod of lowering cholesterol, triglycerides, or LDL levels; a methodof treating or preventing discholesterolemia, or dislipidemia; a methodof treating or preventing cardiovascular disease, atherosclerosis,hypertension, peripheral vascular disease, restenosis or vasospasm; amethod of treating impaired cognition or providing neuroprotection; amethod of treating neurodegenerative disorders, including but notlimited to Alzheimer's disease, Huntington's disease, Parkinson'sdisease or other dementias; a method of treating a spinal cord injury; amethod of treating or preventing cognitive decline, stroke, or anxiety;a method of treating or preventing free radical induced disease states;a method of treating or preventing vaginal atrophy, vulvar atrophy,atrophic vaginitis, vaginal dryness, pruritus, dyspareunia, frequenturination, urinary incontinence, or urinary tract infections; a methodof treating or preventing vasomotor symptoms including but not limitedto flushing or hot flashes; a method of preventing conception; a methodof treating or preventing endometriosis; a method of treating orpreventing arthritis, including but not limited to rheumatoid arthritis,osteoarthritis, arthropathies; a method of treating or preventingpsoriasis or dermatitis; a method of treating or preventing asthma, orpleurisy; a method of treating or preventing multiple sclerosis,systemic lupus erthematosis, uveitis, sepsis, or hemmorhagic shock; amethod of treating or preventing type II diabetes; a method for treatingacute and chronic inflammation of any type; a method of treating orpreventing lung disorders such as asthma or chronic obstructivepulmonary disease; a method of treating or preventing acute or chronicpain, including neuropathic pain; and a method of treating or preventingophthalmologic disorders including but not limited to glaucoma, dry eye,macular degeneration. In other embodiments, methods of modulating, orspecifically agonizing, the Estrogen receptors by administering aneffective amount of a compound of Formula I or II are provided.

Another embodiment is a pharmaceutical composition comprising a compoundof Formula I or II as described above, and a physiologically acceptablecarrier, diluent, or excipient, or a combination thereof.

The term “pharmaceutical composition” refers to a mixture of a compounddisclosed herein with other chemical components, such as diluents orcarriers. The pharmaceutical composition facilitates administration ofthe compound to an organism. Multiple techniques of administering acompound exist in the art including, but not limited to, oral,injection, aerosol, parenteral, and topical administration.Pharmaceutical compositions can also be obtained by reacting compoundswith inorganic or organic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and thelike.

The term “carrier” defines a chemical compound that facilitates theincorporation of a compound into cells or tissues. For example dimethylsulfoxide (DMSO) is a commonly utilized carrier as it facilitates theuptake of many organic compounds into the cells or tissues of anorganism.

The term “diluent” defines chemical compounds diluted in water that willdissolve the compound of interest as well as stabilize the biologicallyactive form of the compound. Salts dissolved in buffered solutions areutilized as diluents in the art. One commonly used buffered solution isphosphate buffered saline because it mimics the salt conditions of humanblood. Since buffer salts can control the pH of a solution at lowconcentrations, a buffered diluent rarely modifies the biologicalactivity of a compound.

The term “physiologically acceptable” defines a carrier or diluent thatdoes not abrogate the biological activity and properties of thecompound.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orsuitable carriers or excipient(s). Techniques for formulation andadministration of the compounds of the instant application may be foundin “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton,Pa., 18th edition, 1990, which is hereby incorporated by reference inits entirety.

Suitable routes of administration may, for example, include oral,rectal, transmucosal, or intestinal administration; parenteral delivery,including intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intranasal, intraocular injections or as an aerosolinhalant.

Alternately, one may administer the compound in a local rather thansystemic manner, for example, via injection of the compound directlyinto the area of pain or inflammation, often in a depot or sustainedrelease formulation. Furthermore, one may administer the drug in atargeted drug delivery system, for example, in a liposome coated with atissue-specific antibody. The liposomes will be targeted to and taken upselectively by the organ.

The pharmaceutical compositions disclosed herein may be manufactured ina manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or tableting processes.

Pharmaceutical compositions for use in accordance with the presentdisclosure thus may be formulated in conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries, which facilitate processing of the active compounds intopreparations, which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Any of the well-knowntechniques, carriers, and excipients may be used as suitable and asunderstood in the art; e.g., as disclosed in Remington's PharmaceuticalSciences, cited above.

For injection, the agents disclosed herein may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHank's solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants appropriate to the barrier to bepermeated are used in the formulation. Such penetrants are generallyknown in the art.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds disclosedherein to be formulated as tablets, pills, dragees, capsules, liquids,gels, syrups, slurries, suspensions and the like, for oral ingestion bya patient to be treated. Pharmaceutical preparations for oral use can beobtained by mixing one or more solid excipient with pharmaceuticalcombination disclosed herein, optionally grinding the resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients are, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as,for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations, which can be used orally, include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to thepresent disclosure are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances, which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents, which increase the solubility of thecompounds to allow for the preparation of highly, concentratedsolutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

A pharmaceutical carrier for the hydrophobic compounds disclosed hereinis a co-solvent system comprising benzyl alcohol, a nonpolar surfactant,a water-miscible organic polymer, and an aqueous phase. A commonco-solvent system used is the VPD co-solvent system, which is a solutionof 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate80™, and 65% w/v polyethylene glycol 300, made up to volume in absoluteethanol. Naturally, the proportions of a co-solvent system may be variedconsiderably without destroying its solubility and toxicitycharacteristics. Furthermore, the identity of the co-solvent componentsmay be varied: for example, other low-toxicity nonpolar surfactants maybe used instead of Polysorbate 80™; the fraction size of polyethyleneglycol may be varied; and other biocompatible polymers may replacepolyethylene glycol, e.g., polyvinyl pyrrolidone. Alternatively, otherdelivery systems for hydrophobic pharmaceutical compounds may beemployed. Liposomes and emulsions are well known examples of deliveryvehicles or carriers for hydrophobic drugs. Certain organic solventssuch as dimethylsulfoxide also may be employed, although usually at thecost of greater toxicity. Additionally, the compounds may be deliveredusing a sustained-release system, such as semipermeable matrices ofsolid hydrophobic polymers containing the therapeutic agent. Varioussustained-release materials have been established and are well known bythose skilled in the art. Sustained-release capsules may, depending ontheir chemical nature, release the compounds for a few weeks up to over100 days. Depending on the chemical nature and the biological stabilityof the therapeutic reagent, additional strategies for proteinstabilization may be employed.

Many of the compounds used in the pharmaceutical combinations disclosedherein may be provided as salts with pharmaceutically compatiblecounterions. Pharmaceutically compatible salts may be formed with manyacids, including but not limited to hydrochloric, sulfuric, acetic,lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble inaqueous or other protonic solvents than are the corresponding free acidsor base forms.

Pharmaceutical compositions suitable for use in the methods disclosedherein include compositions where the active ingredients are containedin an amount effective to achieve its intended purpose. Morespecifically, a therapeutically effective amount means an amount ofcompound effective to prevent, alleviate or ameliorate symptoms ofdisease or prolong the survival of the subject being treated.Determination of a therapeutically effective amount is well within thecapability of those skilled in the art, especially in light of thedetailed disclosure provided herein.

The exact formulation, route of administration and dosage for thepharmaceutical compositions disclosed herein can be chosen by theindividual physician in view of the patient's condition. (See e.g.,Fingl et al. 1975, in “The Pharmacological Basis of Therapeutics”,Chapter 1, which is hereby incorporated by reference in its entirety).Typically, the dose range of the composition administered to the patientcan be from about 0.5 to 1000 mg/kg of the patient's body weight, or 1to 500 mg/kg, or 10 to 500 mg/kg, or 50 to 100 mg/kg of the patient'sbody weight. The dosage may be a single one or a series of two or moregiven in the course of one or more days, as is needed by the patient.Where no human dosage is established, a suitable human dosage can beinferred from ED₅₀ or ID₅₀ values, or other appropriate values derivedfrom in vitro or in vivo studies, as qualified by toxicity studies andefficacy studies in animals.

Although the exact dosage will be determined on a drug-by-drug basis, inmost cases, some generalizations regarding the dosage can be made. Thedaily dosage regimen for an adult human patient may be, for example, anoral dose of between 0.1 mg and 500 mg of each ingredient, preferablybetween 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous,subcutaneous, or intramuscular dose of each ingredient between 0.01 mgand 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of eachingredient of the pharmaceutical compositions disclosed herein or apharmaceutically acceptable salt thereof calculated as the free base,the composition being administered I to 4 times per day. Alternativelythe compositions disclosed herein may be administered by continuousintravenous infusion, preferably at a dose of each ingredient up to 400mg per day. Thus, the total daily dosage by oral administration of eachingredient will typically be in the range 1 to 2000 mg and the totaldaily dosage by parenteral administration will typically be in the range0.1 to 400 mg. In some embodiments, the compounds will be administeredfor a period of continuous therapy, for example for a week or more, orfor months or years.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety, which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). The MECwill vary for each compound but can be estimated from in vitro data.Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. However, HPLC assays orbioassays can be used to determine plasma concentrations.

Dosage intervals can also be determined using MEC value. Compositionsshould be administered using a regimen, which maintains plasma levelsabove the MEC for 10-90% of the time, preferably between 30-90% and mostpreferably between 50-90%.

In cases of local administration or selective uptake, the effectivelocal concentration of the drug may not be related to plasmaconcentration.

The amount of composition administered will, of course, be dependent onthe subject being treated, on the subject's weight, the severity of theaffliction, the manner of administration and the judgment of theprescribing physician.

The compositions may, if desired, be presented in a pack or dispenserdevice, which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. The pack or dispensermay also be accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, may be the labeling approvedby the U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. Compositions comprising a compound disclosedherein formulated in a compatible pharmaceutical carrier may also beprepared, placed in an appropriate container, and labeled for treatmentof an indicated condition.

It will be understood by those of skill in the art that numerous andvarious modifications can be made without departing from the spirit ofthe present disclosure. Therefore, it should be clearly understood thatthe forms disclosed herein are illustrative only and are not intended tolimit the scope of the present disclosure.

EXAMPLES

Embodiments of the present invention are disclosed in further detail inthe following examples, which are not in any way intended to limit thescope of the invention.

Example 1 General Analytical LC-MS Procedure

Procedure 1 (AP1): The analysis was performed on a combinedprep/analytical Waters/Micromass system consisting of a ZMD singlequadropole mass spectrometer equipped with electro-spray ionizationinterface. The HPLC system consisted of a Waters 600 gradient pump withon-line degassing, a 2700 sample manager and a 996 PDA detector.

Separation was performed on an X-Terra MS C18, 5 μm 4.6×50 mm column.Buffer A: 10 mM ammonium acetate in water, buffer B: 10 mM ammoniumacetate in acetonitrile/water 95/5. A gradient was run from 30% B to 100% B in 10 min, dwelling at 100% B for 1 min, and re-equilibrating for6 min. The system was operated at 1 ml/min.

Procedure 2 (AP2): The analysis was performed on a combinedprep/analytical Waters/Micromass system consisting of a ZMD singlequadropole mass spectrometer equipped with electro-spray ionizationinterface. The HPLC system consisted of a Waters 600 gradient pump withon-line degassing, a 2700 sample manager and a 996 PDA detector.

Separation was performed on an X-Terra MS C18, 5 μm 4.6×50 mm column.Buffer A: 10 mM ammonium acetate in water, buffer B: 10 mM ammoniumacetate in acetonitrile/water 95/5. A gradient was run from 30% B to100% B in 7 min, dwelling at 100% B for 1 min, and re-equilibrating for5.5 min. The system was operated at 1 ml/min.

Example 2 General Gas Chromatography (GC) Procedure

GC method 50 was used. Method 50 starts at 50° C. and has a gradient of20° C./min until 250° C. then holds the temperature for 5 minutes. Theanalysis was performed on an Aglient 6850 series GC system withcapillary S/SL inlet and FID with EPC installation. The column was a 10m×0.32 mm×0.25 μm HP5 column.

Example 3 Synthesis of trifluoromethanesulfonates, General Procedure 1(GP1)

Trifluoromethanesulfonates were prepared according to literatureprocedure by McMurry and Scott (McMurry, J. E.; Scott, W. J.,Tetrahedron letters, 1983, 979-982).

4-isoPropyl-cyclehexenyl-1-trifluoromethanesulfonate

The title compound was prepared according to GP1 from4-ipropylcyclohexanone (10.0 g, 71 mmol). Crude yield: 14.1 g. ¹H-NMR(400 MHz, CDCl₃) d 5.78-5.69 (m, 1H), 2.42-2.14 (m, 3H), 1.98-1.84 (m,2H), 1.60-1.2 (m, 4H), 0.94-0.88 (m, 6H).

1-Cyclohexenyl-1- trifluoromethanesulfonate

The title compound was prepared according to GP1 from cyclohexanone (9.8g, 100 mmol). Crude yield: 14.0 g (83% pure by ¹H-NMR). ¹H-NMR (400 MHz,CDCl₃) d 5.79-5.73 (m, 1H), 2.36-2.28 (m, 2H), 2.23-2.14 (m, 2H),1.83-1.75 (m, 2H), 1.66-1.56 (m, 2H).

4-Trifluoromethyl-cyclohexenyl-1-trifluoromethanesulfonate

The title compound was prepared according to GP1 from4-(trifluoromethyl)cyclohexanone (3.0 g, 18 mmol). Crude yield: 1.9 g.GC-FID R_(t): 1.16 min (Method50)

1-Cycloheptenyl-1-trifluoromethanesulfonate

The title compound was prepared according to GP1 from cycloheptanone(2.2 g, 20 mmol). Crude yield: 3.7 g.

¹H-NMR (400 MHz, CDCl₃) d 5.86-5.74 (m, 1H), 2.51-2.40 (m, 2H),2.14-2.06 (m, 2H), 1.77-1.49 (m, 6H).

Example 4 Suzuki Coupling, General Procedure 2 (GP2)

The appropriate boronic acid (4.4 mmol) was dissolved in dry THF (20 mL)and cyclohexenyl triflate (4.0 mmol) and KF (13.2 mmol) was added. Thesolution was degassed and kept under Argon and PdCl₂(dppf) (65.3 mg,0.08 mmol) was added. The reaction was shaken overnight at rt afterwhich time they were filtered through celite, rinsed with EtOAc andsubjected to column chromatography (silica, hexane).

2,6-Difluorophenyl cyclohexene

The title compound was prepared according to GP2. Yield: 551 mg (2.84mmol, 71%). ¹H-NMR (400 MHz, CDCl₃) d 7.17-7.10 (m, 1H), 6.88-6.81 (m,2H), 5.80 (m, 1H), 2.26-2.19 (m, 4H), 1.78-1.70 (m, 4H).GC Analysis:R_(t)=2.55 min (Method 50), 97%.

2,5-Difluorophenyl cyclohexene

The title compound was prepared according to GP2. Yield: 596 mg (3.07mmol, 77%). ¹H-NMR (400 MHz, CDCl₃) d 6.88-6.81 (m, 2H), 6.78-6.73 (m,1H), 5.88 (m, 1H), 2.26-2.23 (m, 2H), 2.13-2.09 (m, 2H), 1.68-1.64 (m,2H), 1.61-1.57 (m, 2H). GC Analysis (method 50): R_(t)=2.77 min, 91%.

2,4-Difluorophenyl cyclohexene

The title compound was prepared according to GP2. Yield: 290 mg (1.49mmol, 37%), ¹H-NMR (400 MHz, CDCl₃) d 7.12 (ddd, 1H, J=8.6 Hz, 6.6 Hz,6.6 Hz), 6.77-6.68 (m, 2H), 5.82 (m, 1H), 2.29-2.25 (m, 2H), 2.16-2.11(m, 2H), 1.73-1.59 (m, 4H). GC Analysis (method 50): R_(t)=2.62 min,98%.

5-Chloro-2-fluorophenyl cyclohexene

The title compound was prepared according to GP2. Yield: 701 mg (3.32mmol, 83%). ¹H-NMR (400 MHz, CDCl₃) d 7.15 (dd, 1H, J=6.65 Hz, 2.74 Hz),7.06 (m, 1H), 6.88 (dd, 1H, J=10.27 Hz, 8.70 Hz), 5.90 (m, 1H),2.28-2.26 (m, 2H), 2.17-2.13 (m, 2H), 1.71-1.67 (m, 2H), 1.65-1.60 (m,2H). GC Analysis: R_(t)=3.88 min, 94%.

Example 5 Negishi Coupling, General Procedure 3 (GP3)1-(1-Cyclohexen-1-yl)-3-methoxy-benzene

In a dry and argon flushed two neck flask, tris(dibenzylidedeacetone)dipalladium (275 mg, 0.3 mmol) and tri-2-furylphosphine (278 mg, 1.2mmol) was dissolved in N-methylpyrrolidone. Tetrabutyl ammonium iodide(2.21 g, 6.0 mmol) and 1-cyclohexenyl-1-trifluoromethanesulfonate (1.85g, 6.0 mmol) were added to the reaction mixture followed by phenylzincbromide(12 mL, 1.0 M, 12 mmol) and the reaction mixture was leftstirring at room temperature over night. The reaction was quenched withsaturated ammonium chloride solution. The product was filtered throughcelite, taken up in ethyl acetate and washed with brine, dried overNa₂SO₄, and concentrated in vacuo. The title compound was obtained andpurified by flash chromatography (silica, 0-10% EtOAc in heptane).Yield: 700 mg. ¹H-NMR (400 MHz, CDCl₃) δ: 7.23 (t, J=7.8 Hz, 1H), 7.04(d, J=7.8 Hz, 1H), 6.98 (s, 1H), 6.81 (d, J=7.8 Hz, 1H), 6.18-6.17 (m,1H), 3.82 (s, 3H), 2.45-2.42 (m, 2H), 2.24-2.21 (m, 2H), 1.83-1.79 (m,2H), 1.72-1.68 (m, 2H).

4-(Trifluoromethyl)-1-cyclohexen-1-yl]-benzene

The title compound was prepared according to GP3 from4-(trifluoromethyl)-1-cyclohexenyl-1-trifluoromethanesulfonate (475 mg,1.6 mmol) and phenylzinc bromide (3.2 mL, 1.0 M, 3.2 mmol). The productwas purified by flash chromatography (silica, heptane). Yield: 284 mg.¹H-NMR (400 MHz, CDCl₃) δ: 7.32-7.15 (m, 5H), 6.01-5.98 (m, 1H),2.58-2.07 (m, 6H), 1.71-1.58 (m, 1H).

1-Fluoro-4-[4-(trifluoromethyl)-1-cyclohexen-1-yl]-benzene

The title compound was prepared according to GP3 from4-(trifluoromethyl)-1-cyclohexenyl-1-trifluoromethanesulfonate (475 mg,1.6 mmol) and 4-fluorophenylzinc bromide (3.2 mL, 1.0 M, 3.2 mmol). Theproduct was purified by flash chromatography (silica, heptane). Yield:271 mg. ¹H-NMR (400 MHz, CDCl₃) δ: 7.38-7.32 (m, 2H), 7.07-6.98 (m, 2H),6.02-5.99 (m, 1H), 2.61-2.17 (m, 6H), 1.76-1.63 (m, 1H).

1-Fluoro-3-[4-(trifluoromethyl)-1-cyclohexen-1-yl]-benzene)

The title compound was prepared according to GP3 from4-(trifluoromethyl)-1-cyclohexenyl-1-trifluoromethanesulfonate (475 mg,1.6 mmol) and 3-fluorophenylzinc bromide (3.2 mL, 1.0 M, 3.2 mmol). Theproduct was purified by flash chromatography (silica, heptane). Yield:363 mg. ¹H-NMR (400 MHz, CDCl₃) δ: 7.35-6.92 (m, 4H), 6.15-6.11 (m, 1H),2.62-2.15 (m, 6H), 1.75-1.64 (m, 1H).

1-(Cyclohexen-1-yl)-2-fluorobenzene

The title compound was prepared according to GP3 from1-cyclohexenyl-1-trifluoromethanesulfonate (1.84 g, 8.0 mmol) and2-fluorophenylzinc bromide (16 mL, 1.0 M, 32 mmol). The product waspurified by flash chromatography (silica, heptane). Yield: 678 mg.¹H-NMR (400 MHz, CDCl₃) δ: 7.30-6.97 (m, 4H), 5.96-5.90 (m, 1H),2.40-2.33 (m, 2H), 2.23-2.18 (m, 2H), 1.79-1.70 (m, 2H), 1.70-1.64 (m,2H).

4-(1-Cyclohexen-1-yl)-1,2-difluoro-benzene

The title compound was prepared according to GP3 from1-cyclohexenyl-1-trifluoromethanesulfonate (1.84 g, 8.0 mmol) and3,4-difluorophenylzinc bromide (32 mL, 0.5 M, 16 mmol). The product waspurified by flash chromatography (silica, heptane). Yield: 1.31 g.¹H-NMR (400 MHz, CDCl₃) δ: 7.20-7.00 (m, 3H), 6.07-6.00 (m, 1H),2.38-2.30 (m, 2H), 2.24-2.18 (m, 2H), 1.82-1.66 (m, 4H).

1-(1-Cyclohexen-1-yl)-3,5-difluoro-benzene

The title compound was prepared according to GP3 from1-cyclohexenyl-1-trifluoromethanesulfonate (1.84 g, 8.0 mmol) and3,5-difluorophenylzinc bromide (32 mL, 0.5 M, 16 mmol). The product waspurified by flash chromatography (silica, heptane). Yield: 934 mg.GC-FIDR_(t): 2.96 min (Method50)

1-Fluoro-2-[4-(1-i-propyl)-1-cyclohexen-1-yl]-benzene

The title compound was prepared according to GP3 from4-(1-i-propyl)-1-cyclohexenyl-1-trifluoromethanesulfonate (2.18 g, 8.0mmol) and 2-fluorophenylzinc iodide (32 mL, 0.5 M, 16.0 mmol). Theproduct was purified by flash chromatography (silica, heptane). Yield:1.15 g. ¹H-NMR (400 MHz, CDCl₃) δ: 7.30-7.01 (m, 4H), 5.97-5.93 (m, 1H),2.51-1.34 (m, 8H), 0.98-0.88 (m, 6H).

1-Fluoro-3-[4-(1-i-propyl)-1-cyclohexen-1-yl]-benzene

The title compound was prepared according to GP3 from4-(1-i-propyl)-1-cyclohexenyl-1-trifluoromethanesulfonate (2.18 g, 8.0mmol) and 3-fluorophenylzinc iodide (32 mL, 0.5 M, 16.0 mmol). Theproduct was purified by flash chromatography (silica, heptane). Yield:902 mg. ¹H-NMR (400 MHz, CDCl₃) δ: 7.35-7.12 (m, 3H), 6.92-6.87 (m, 1H),6.18-6.12 (m, 1H), 2.51-1.35 (m, 8H), 0.99-0.95 (m, 6H).

1-Methoxy-3-[4-(1-i-propyl)-1-cyclohexen-1-yl]-benzene

The title compound was prepared according to GP3 from4-(1-i-propyl)-1-cyclohexenyl-1-trifluoromethanesulfonate (2.18 g, 8.0mmol) and 2-methoxyphenylzinc bromide (16 mL, 1.0 M, 16.0 mmol). Theproduct was purified by flash chromatography (silica, heptane). Yield:1.63 g. GC-FID R_(t): 6.07 min (Method50)

Example 6 Vinylaromatic Compounds, General Procedure 4 (GP4)

The vinylaromatic compounds were prepared as exemplified below usingcycloheptanone and phenylmagnesium chloride.

1-Phenylcycloheptene, General Procedure 4 (GP4)

Mesitylmagnesium bromide (18.0 mL, 18.0 mmol, 1.0 M in THF) was addedover 15 minutes to a solution of cycloheptanone (2.0 g, 17.8 mmol) anddiphenyl chlorophosphate (1.1 eq.) in THF (5 mL) at 0° C. The solutionwas stirred at 0° C. for 30 min, whereafter the solution was allowed toreach room temperature. After stirring the solution for 30 min,dichlorobis(triphenylphosphine)palladium (126 mg, 1 mol %) was added andthe solution was warmed to 65° C. Phenylmagnesium chloride (10.8 mL, 1.2equivalents in THF) was added over 10 minutes, resulting in a gentlereflux of the solvent. After stirring at 65° C. for 30 minutes, themixture was cooled to rt and poured into a mixture of 3 N HCl (30 mL)and pentane (30 mL). The phases were separated, and the aqueous portionwas extracted with pentane (30 mL). The combined organic phase waswashed sequentially with 3 N HCl (20 mL), 3 M NaOH (2×20 mL), and brine(20 mL), and dried over MgSO4. Evaporation of the solvent followed bydistillation using a Kugelrohr apparatus (oven temperature 100-140° C.,0.065 torr) yielded 1-phenylcycloheptene (1.29 g, 43%).

¹H-NMR (400 MHz, CDCl₃) δ 7.37-7.20 (m, 5H), 6.11 (t, 1H), 2.65 (m, 2H),2.30 (m, 2H), 1.88 (m, 2H), 1.70 (m, 2H), 1.60 (m, 2H).

¹³C-NMR (100 MHz, CDCl₃) δ 145.2, 140.5, 130.5, 128.3 (2C), 126.5, 126.0(2C), 33.0, 32.9, 29.0, 27.1, and 27.0.

1-Phenylcycloheptene was also synthesized according to GP3

1-(3-Fluorophenyl)-cycloheptene

1-(3-Fluorophenyl)-cycloheptene was prepared according to GP4 and GP3described above and isolated by column chromatography. ¹H-NMR (400 MHz,CDCl₃) δ 7.27-7.20 (m, 1H), 7.10 (m, 1H), 7.0 (m, 1H), 6.95-6.85 (m,1H), 6.10 (t, 1H, J=8.0 Hz), 2.6 (m, 2H), 2.33-2.23 (m, 2H), 1.89-1.8(m, 2H), 1.7-1.5 (m, 4H). ¹³C-NMR (100 MHz, CDCl₃) δ 163.0 (d, J=242Hz), 147.7 (d, J=20 Hz), 144.3, 131.7, 129.7 (d, J=20 Hz), 121.5, 113.1(d, J=22 Hz), 112.7 (d, J=22 Hz), 32.9, 32.8, 29.0, 27.0, 26.9.

1-(2-Fluorophenyl)-cycloheptene

1-(2-Fluorophenyl)-cycloheptene was prepared according to GP3 describedabove and isolated by column chromatography. R_(f)=0.85 (heptane).

1-(4-Fluorophenyl)-cycloheptene

1-(4-Fluorophenyl)-cycloheptene was prepared according to GP3 and GP4described above and isolated by column chromatography.

¹H-NMR (400 MHz, CDCl₃) δ 7.35-7.25 (m, 2H), 7.00-6.90 (m, 2H), 6.05 (t,1H, J=8.0 Hz), 2.60 (m, 2H), 2.33-2.23 (m, 2H), 1.90-1.80 (m, 2H),1.70-1.50 (m, 4H).

¹³C-NMR (100 MHz, CDCl₃) δ 161.9 (d, J=244 Hz), 144.2, 141.3 (d, J=3Hz), 130.5, 127.4 (d, 2C, J=8 Hz), 115.0 (d, 2C, J=21 Hz), 33.2, 32.9,29.0, 27.1, 27.0.

1-Phenylcyclooctene

1-Phenylcyclooctene was prepared according to GP3 and GP4 describedabove and isolated by Kugelrohr distillation (oven temperature 120-140°C., 0.065 torr). Yield (1.5 g, 60%).

¹H-NMR (400 MHz, CDCl₃) δ 7.44-7.39 (m, 2H), 7.33-7.18 (m, 3H), 6.01 (t,1H, J=8.0 Hz), 2.67-2.61 (m, 2H), 2.34-2.26 (m, 2H), 1.70-1.50 (m, 8H).¹³C-NMR (100 MHz, CDCl₃) δ 143.4, 140.5, 128.4 (2C), 128.2, 126.6, 126.0(2C), 30.2, 29.7, 28.7, 27.6, 27.1, 26.4.

1-Methoxy-4-(1-phenyl-cyclohexyl)-benzene, Procedure A

A mixture of AuCl₃ (7.6 mg, 0.025 mmol) and AgOTf (19.3 mg, 0.075 mmol)was stirred in dichloromethane (2 mL) for 30 min. Anisole (54 mg, 0.5mmol) and 1-Phenyl-1-cyclohexene (158 mg, 1 mmol) were then addedsequentially. The resulting mixture was stirred at room temperatureovernight. Evaporation of the solvent under reduced pressure gave 130 mgof crude material. Flash chromatography (heptane:ethyl acetate 95:5)afforded 90 mg of a as a colorless oil. R_(f)=0.33 (heptane:ethylacetate 95:5). ¹H-NMR (400 MHz, CDCl₃): 7.27-7.25 (m, 4H), 7.19 (d, 2H,J=8.8 Hz), 7.12 (m, 1H), 6.81 (d, 2H, J=8.8 Hz), 3.77 (s, 3H), 2.30-2.20(m, 4H), 1.62-1.44 (m, 6H).

1-Methoxy-4-(1-phenyl-cyclohexyl)-benzene (B), Procedure B

4-(1-phenylcyclohexyl)phenol (20 mg, 0.08 mmol) was dissolved in DMF (2mL). A suspension of NaH in oil (60%, 5 mg, 0.125 mmol) was added. Afterstirring for 5 minutes methyl iodide (0.05 mL; 0.8 mmol) was added. Thereaction mixture was stirred for 2 h. (tlc indicated full conversion ofthe starting material) then quenched with water (10 mL). Dichloromethane(10 mL) was added. The mixture was shaken and the organic phaseseparated off, dried (Na2SO₄) and concentrated to syrup. The titleproduct was afforded after work-up by flash-chromatography (eluentdichloromethane). Yield: 20 mg, quantitatively. LC-MS purity (UV/MS):100/-, R_(t) 6.48 min. ¹H NMR data were in accordance with the datawritten above.

Example 7 General Procedure 5 (GP5) 4-(1-Phenylcyclohexyl)phenol(ERB-002)

1-Phenyl-1-cyclohexene (1 g, 6.3 mmol), phenol (1.5 g, 15.9 mmol) andBF₃.H₃PO₄ (0.05 mL) were mixed and shaken at 80° C. overnight.Dichloromethane (30 mL) was added and the organic phase was washed withsaturated NaHCO₃ (aq.) (2×10 mL), dried (Na₂SO₄) and concentrated. Thetitle compound was crystallised from a mixture of methanol and water.Yield: 1040 mg. ¹H NMR (400 MHz, CDCl₃): d 7.28-7.25 (m, 4H), 7.16-7.10(m, 3H), 6.75-6.70 (m, 2H), 4.51 (br. s, 1H), 2.28-2.22 (m, 4H),1.60-1.52 (m, 4H), 1.52-1.45 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d153.25, 149.15, 141.22, 128.63, 128.39, 127.29, 125.55, 115.21, 45.89,37.50, 26.63, 23,14. LC-MS purity (UV/MS): 100/100%, R. 5.07 min, M−1:251.62.

4-(1-(2-Fluoro-phenylcyclohexyl)phenol (ERB-003)

The title compound was prepared according to GP5 from1-(cyclohexen-1-yl)-2-fluorobenzene (400 mg, 1.99 mmol). Yield: 0.488 gwhite powder. ¹H NMR (400 MHz, CDCl₃): d 7.40 (ddd, 2.3 Hz, 8.1 Hz, 8.3Hz, 1H), 7.18-7.06 (m, 3H), 6.88 (ddd, 2.3 Hz, 8.1 Hz, 12.7 Hz, 1H),6.74-6.69 (m, 2H), 4.51 (br. s, 1H), 2.48-2.36 (m, 2H), 2.22-2.13 (m,2H), 1.67-1.41 (m, 6H). LC-MS purity (UV/MS): 100/100%, R_(t) 4.98 min,M−1: 269.16.

4-(1-(3,5-Difluoro-phenylcyclohexyl)phenol (ERB-008 )

The title compound was prepared according to GP5 from1-(cyclohexen-1-yl)-3,5-difluorobenzene (400 mg, 1.99 mmol). Yield: 330mg white powder. LC-MS purity (UV/MS): 100/100%, R_(t) 5.08 min, M−1:287.17.

4-(1-(3,4-Difluoro-phenylcyclohexyl)phenol (ERB-009)

The title compound was prepared according to GP5 from1-(cyclohexen-1-yl)-3,4-difluorobenzene (400 mg, 1.99 mmol). Yield: 230mg white powder. ¹H NMR (400 MHz, CDCl₃): d 7.18-7.12 (m, 2H), 7.12-6.95(m, 3H), 6.84-6.76 (m, 2H), 5.44 (br. s, 1H), 2.40-2.05 (m, 4H),1.67-1.30 (m, 6H). LC-MS purity (UV/MS): 100/98%, R_(t) 5.08 min, M−1:287.22.

4-[1-(2,6-Difluoro-phenyl)-cyclohexyl]-phenol (ERB-010)

The title compound was prepared according to GP5 from1-(cyclohexen-1-yl)-2,6-difluorobenzene (200 mg, 1.0 mmol). Yield: 218mg white powder. ¹H NMR (400 MHz, CDCl₃): d 7.24-7.18 (m, 2H), 7.18-6.98(m, 1H), 6.82-6.76 (m, 2H), 6.72-6.68 (m, 2H), 5.48 (br. s, 1H),2.85-2.76 (m, 2H), 1.95-1.85 (m, 2H), 1.76-1.64 (m, 2H), 1.64-1.34 (m,4H). LC-MS purity (UV/MS): 100/100%, R_(t) 5.08 min, M−1: 287.60.

4-(1-Phenyl-[4-(trifluoromethyl)-cyclohexyl])-phenol (ERB-030)

The title compound was prepared according to GP5 from[4-(trifluoromethyl)-1-cyclohexen-1-yl]-benzene (200 mg, 1.0 mmol).Yield: 228 mg.

ERB-030: ¹H NMR (400 MHz, CDCl₃): d 7.35-7.08 (m, 7H), 6.82-6.77 (m,2H), 4.80 (br. s, 1H), 2.80-2.75 (m, 2H), 2.23-2.10 (m, 1H), 1.99-1.82(m, 4H), 1.62-1.55 (m, 2H). LC-MS purity (UV/MS): 100 /100 R_(t) 9.16min, M−1: 319.19.

Isomer of ERB-030: ¹H NMR (400 MHz, CDCl₃): d 7.38-7.15 (m, 5H),7.10-6.98 (m, 2H), 6.72-6.64 (m, 2H), 4.67 (br. s, 1H), 2.82-2.71 (m,2H), 2.21-2.15 (m, 1H), 2.00-1.82 (m, 4H), 1.62-1.50 (m, 2H). LC-MSpurity (UV/MS): 100/100, R_(t) 9.21 min, M−1: 319.19.

4-(1-(4-Flourophenyl)-[4-(trifluoromethyl)-cyclohexyl])-phenol (ERB-031)

The title compound was prepared according to GP5 from4-fluoro-[4-(trifluoromethyl)-1-cyclohexen-1-yl]-benzene (200 mg, 1.0mmol). Yield: 221 mg.

ERB-031: ¹H NMR (400 MHz, CDCl₃): d 7.18-7.11 (m, 2H), 7.10-7.07 (m,2H), 6.92-6.87 (m, 2H), 6.83-6.80 (m, 2H), 4.80 (br. s, 1H), 2.72-2.64(m, 2H), 2.22-2.08 (m, 1H), 1.95-1.85 (m, 4H), 1.59-1.47 (m, 2H). LC-MSpurity (UV/MS): 100/100%, R_(t) 9.28 min, M−1: 337.17.

Isomer of ERB-031: ¹H NMR (400 MHz, CDCl₃): d 7.32-7.24 (m, 2H),7.08-6.96 (m, 2H), 6.72-6.66 (m, 2H), 4.73 (br. s, 1H), 2.74-2.66 (m,2H), 2.22-2.08 (m, 1H), 1.96-1.86 (m, 4H), 1.56-1.44 (m, 2H). LC-MSpurity (UV/MS): 100/100%, R_(t) 9.24 min, M−1: 337.17.

4-(1-(3-Flourophenyl)-[4-(trifluoromethyl)-cyclohexyl])-phenol (ERB-032)

The title compound was prepared according to GP5 from4-fluoro-[4-(trifluoromethyl)-1-cyclohexen-1-yl]-benzene (200 mg, 1.0mmol). Yield: 221 mg. The diastereomers were separated by flashchromatography.

ERB-032: ¹H NMR (400 MHz, CDCl₃) d 7.48-7.44 (m, 1H), 7.24-7.13 (m, 2H),7.08-7.03 (m, 2H), 6.96-6.90 (m, 1H), 6.72-6.67 (m, 2H), 4.73 (br. s,1H), 2.94-2.86 (m, 2H), 2.20-2.08 (m, 1H), 1.98-1.90 (m, 2H), 1.88-1.78(m, 2H), 1.60-1.48 (m, 2H). LC-MS purity (UV/MS): 100/100%, R_(t) 9.21min, M−1: 337.17.

Isomer of ERB-032: ¹H NMR (400 MHz, CDCl₃): d 7.26-7.21 (m, 2H),7.18-7.11 (m, 2H), 7.05-7.00 (m, 1H), 6.90-6.85 (m, 1H), 6.80-6.76 (m,2H), 4.78 (br. s, 1H), 2.90-2.81 (m, 2H), 2.22-2.10 (m, 1H), 2.10-1.99(m, 2H), 1.90-1.84 (m, 2H), 1.62-1.48 (m, 2H). LC-MS purity (UV/MS):100/100%, R_(t) 9.28 min, M−1: 337.17.

4-[1-(2-Fluoro-phenyl)-4-isopropyl-cyclohexyl]-phenol (ERB-039)

The title compound was prepared according to GP5 from1-fluoro-2-[4-(1-i-propyl)-1-cyclohexen-1-yl]-benzene (200 mg, 1.0mmol). Yield: 180 mg. The diastereomers were separated by flashchromatography

ERB-039: ¹H NMR (400 MHz, CDCl₃): d 7.68-7.52 (m, 1H), 7.24-7.10 (m,2H), 7.10-7.04 (m, 2H), 6.95-6.86 (m, 1H), 6.71-6.64 (m, 2H), 4.66 (br.s, 1H), 2.84-2.75 (m, 3H), 1.90-1.73 (m, 4H), 1.40-1.25 (m, 3H), 0.83(d, 6H, 7 Hz). LC-MS purity (UV/MS): 100/100%, R_(t) 6.10 min, M−1:311.51.

Isomer of ERB-039: ¹H NMR (400 MHz, CDCl₃) d 7.30-7.22 (m, 3H),7.17-7.08 (m, 1H), 7.07-7.00 (m, 1H), 6.90-6.80 (m, 1H), 6.78-6.74 (m,2H), 4.58 (br. s, 1H), 2.82-2.74 (m, 2H), 2.04-1.93 (m, 2H), 1.70-1.64(m, 2H), 1.38-1.12 (m, 4H), 0.83 (d, 6H, 7 Hz). LC-MS purity (UV/MS):100/86%, R_(t) 6.16 min, M−1: 311.52.

4-[1-(3-Fluoro-phenyl)-4-isopropyl-cyclohexyl]-phenol (ERB-037)

The title compound was prepared according to GP5 from1-fluoro-3-[4-(1-i-propyl)-1-cyclohexen-1-yl]-benzene (200 mg, 1.0mmol). Yield: 150 mg. The diastereomers were separated by flashchromatography

ERB-037: ¹H NMR (400 MHz, CDCl₃): d 7.24-7.18 (m, 2H), 7.18-7.12 (m,1H), 6.96-6.92 (m, 1H), 6.89-6.84 (m, 1H), 6.82-6.74 (m, 3H), 4.66 (br.s, 1H), 2.64-2.58 (m, 2H), 1.92-1.82 (m, 2H), 1.73-1.65 (m, 2H),1.38-1.13 (m, 4H), 0.82 (d, 6H, 7 Hz). LC-MS purity (UV/MS): 100/- ,R_(t) 6.87 min, M−1: 311.

Isomer of ERB-037: ¹H NMR (400 MHz, CDCl₃) d 7.29-7.20 (m, 1H),7.14-7.10 (m, 1H), 7.08-7.00 (m, 3H), 6.88-6.81 (m, 1H), 6.70-6.64 (m,2H), 4.58 (br. s, 1H), 2.66-2.58 (m, 2H), 1.94-1.82 (m, 2H), 1.75-1.67(m, 2H), 1.37-1.24 (m, 1H), 1.19-1.10 (m, 3H), 0.82v (d, 6H, 7 Hz).LC-MS purity (UV/MS): 100/100%, R_(t) 6.16 min, M−1: 311.

4-[4-Isopropyl-1-(3-methoxy-phenyl)-cyclohexyl]-phenol (ERB-038)

The title compound was prepared according to GP5 from1-methoxy-3-[4-(1-i-propyl)-1-cyclohexen-1-yl]-benzene (200 mg, 1.0mmol). The diastereomers were separated by flash chromatography

ERB-038: ¹H NMR (400 MHz, CDCl₃): d 7.28-7.20 (m, 2H), 7.08-7.02 (m,2H), 6.96-6.92 (m, 1H), 6.73-6.62 (m, 3H), 4.58 (br. s, 1H), 3.80 (s,3H), 2.68-2.60 (m, 2H), 1.94-1.82 (m, 2H), 1.38-1.08 (m, 4H), 0.82 (d,6H, 7 Hz). LC-MS purity (UV/MS): 100/100, R_(t) 6.87 min, M−1: 323.

Isomer of ERB-038: ¹H NMR (400 MHz, CDCl₃) d 7.29-7.20 (m, 3H),7.19-7.10 (m, 1H), 6.80-6.72 (m, 3H), 6.68-6.60 (m, 1H), 4.60 (br. s,1H), 3.74 (s, 3H), 2.66-2.58 (m, 2H), 1.94-1.83 (m, 2H), 1.38-1.05 (m,4H), 0.80 (d, 6H, 7 Hz). LC-MS purity (UV/MS): 100/100%, R_(t) 6.16 min,M−1: 323.

4-(1-Phenyl-cycloheptyl)-phenol (ERB-012)

The title compound was prepared according to GP5 with a yield of40%-70%. LC-MS purity (UV/MS): 100/100%, R_(t) 5.35 min. ¹H-NMR (400MHz, CDCl₃) δ 7.28-7.10 (m, 5H), 7.04 (d, 2H, J=8.8 Hz), 6.70 (d, 2H,J=8.8 Hz), 4.55 (s, 1H), 2.35-2.20 (m, 4H), 1.78-1.60 (m, 4H), 1.60-1.50(m, 4H).

4-[1-(4-Fluoro-phenyl)-cycloheptyl]-phenol (ERB-013)

The title compound was prepared according to GP5 with a yield of40%-70%. LC-MS purity (UV/MS): 100/100%, R_(t) 9.89 min. ¹H-NMR (400MHz, CDCl₃) δ 7.15 (m, 2H), 7.01 (d, 2H, J=8.7 Hz), 6.95 (m, 2H), 6.75(d, 2H, J=8.7 Hz), 4.55 (br. s, 1H), 2.30-2.20 (m, 4H), 1.75-1.40 (m,8H).

4-[1-(4-Fluoro-phenyl)-cycloheptyl]-benzene-1,2-diol (ERB-014)

The title compound was prepared according to GP5 with a yield of40%-70%. LC-MS purity (UV/MS): 86/100%, R_(t) 9.05 min. ¹H-NMR (400 MHz,CDCl₃) δ 7.17-7.10 (m, 2H), 6.96-6.70 (m, 3H), 6.60 (m, 2H), 5.15-4.85(m, 2-3H), 2.30-2.10 (m, 4H), 1.70-1.40 (m, 8H).

4-[1-(3-Fluoro-phenyl)-cycloheptyl]-phenol (ERB-015)

The title compound was prepared according to GP5 with a yield of40%-70%. LC-MS purity (UV/MS): 99/93%, R_(t) 9.88 min. ¹H-NMR (400 MHz,CDCl₃) δ 7.30-6.68 (m, 4H), 7.12 (d, 2H, J=8.8 Hz), 6.74 (d, 2H, J=8.8Hz), 4.55 (s, 1H), 2.26 (m, 1H), 2.0 (m, 1H), 1.72-1.50 (m, 8H),1.30-1.10 (m, 2H).

4-[1-(2-Fluoro-phenyl)-cycloheptyl]-phenol (ERB-016)

The title compound was prepared according to GP5 with a yield of40%-70%. ¹H-NMR (400 MHz, CDCl₃) δ 7.44 (m, 1H), 7.22-7.10 (m, 2H), 7.02(d, 2H, J=8.8 Hz), 6.92-6.86 (m, 1H), 6.70 (d, 2H, J=8.8 Hz), 4.51 (s,1H), 2.42-2.26 (m, 4H), 1.82-1.52 (m, 8H). ¹³C-NMR (100 MHz, CDCl₃) δ161.7 (d, J=249 Hz), 153.2, 143.2, 137.4 (d, J=11 Hz), 128.0 (d, J=5Hz), 127.9 (d, J=9 Hz), 127.7 (2C), 123.5 (d, J=3 Hz), 116.8 (d, J=24Hz), 114.9 (2C), 48.7 (d, J=2 Hz), 39.4 (d, J=2 Hz), 30.6, 24.6.

4-(1-Phenyl-cyclooctyl)-phenol (ERB-017)

The title compound was prepared according to GP5 with a yield of40%-70%. ¹H-NMR (400 MHz, CDCl₃) δ 7.26-7.10 (m, 5H), 7.09 (d, 2H, J=8.8Hz), 6.71 (d, 2H, J=8.8 Hz), 2.34-2.28 (m, 4H), 1.68-1.54 (m, 6H),1.46-1.38 (m, 4H).

4-(1-Phenyl-cycloheptyl)-benzene-1,2-diol (ERB-035)

The title compound was prepared according to GP5 with a yield of40%-70%. ¹H-NMR (400 MHz, CDCl₃) δ 7.28-7.10 (m, 5H), 6.76-6.72 (m, 1H),6.67-6.63 (m, 2H), 4.90 (bs, 1H), 2.30-2.10 (m, 4H), 1.8-1.4 (m, 8H).

2-Methyl-4-[1-(3-Fluoro-phenyl)-cycloheptyl]-phenol (ERB-036)

The title compound was prepared according to GP5 with a yield of40%-70%. LC-MS purity (UV/MS): 94/100%, R_(t) 10.37 min.

4-(1-(2,4-Difluoro-phenyl)-cyclohexyl)-phenol (ERB-011)

The title compound was prepared according to GP5 with a yield of40%-70%. ¹H-NMR (400 MHz, CDCl₃) δ 7.34 (m, 1H), 7.12 (d, 2H, J=8.4 Hz),6.82 (m, 1H), 6.72 (d, 2H, J=8.4 Hz), 6.64 (m, 1H), 4.50 (s, 1H), 2.36(m, 2H), 2.18 (m, 2H), 1.66-1.40 (m, 6H).

4-(1-(2,5-Difluoro-phenyl)-cyclohexyl)-phenol (ERB-044)

The title compound was prepared according to GP5 with a yield of40%-70%. ¹H-NMR (400 MHz, CDCl₃) δ 7.14 (d, 2H, J=8.8 Hz), 7.14-7.06 (m,1H), 6.83 (m, 2H), 6.73 (d, 2H, J=8.0 Hz), 4.50 (s, 1H), 2.35 (m, 2H),2.20 (m, 2H), 1.66-1.40 (m, 6H).

4-(1-(2-Fluoro-5-chloro-phenyl)-cyclohexyl)-phenol (ERB-045)

The title compound was prepared according to GP5 with a yield of40%-70%. ¹H-NMR (400 MHz, CDCl₃) δ 7.38 (dd, 1H, J=8.0 Hz, 4.4 Hz),7.17-7.09 (m, 1H), 7.14 (d, 2H, J=8.4 Hz), 6.86-6.74 (m, 1H), 6.73 (d,2H, J=8.4 Hz), 4.58 (s, 1H), 2.33 (m, 2H), 2.21 (m, 2H), 1.54 (m, 6H).

Example 8 tert-Butyl1-((4-(1-phenylcyclohexyl)phenoxy)carbonyl)-2-methylpropylcarbamate

To a stirred solution at room temperature of4-(1-phenylcyclohexyl)phenol (311 mg, 1.23 mmol) in dry THF (2 mL) wasadded BocValOH (295 mg, 1.36 mmol) dissolved in THF (2 mL). A solutionof DIC (231 μL; 1.48 mmol) in THF (2 mL) was added drop wise, whichcaused precipitation after a few minutes. After 5 min DMAP (166 mg; 1.36mmol) was added and stirring was continued for 19 h. The reactionmixture was concentrated in vacuo and purified by flash chromatography(eluent: EtOAc (0-10%) in heptane) affording 517 mg (1.14 mmol; 93%) ofcolourless oil. LC-MS purity (UV/MS): 100/100%, R_(t) 6.77 min, M+18:469.53.

Example 9 4-(1-Phenylcyclohexyl)phenyl 2-amino-3-methylbutanoate

To a stirred solution at room temperature of tert-butyl1-((4-(1-phenylcyclohexyl)phenoxy)carbonyl)-2-methylpropylcarbamate (142mg, 0.31 mmol) in dry DCM (3 mL) was added TFA (300 μL), which causedgas evolution. Stirring was continued. After 1 h the reaction mixturewas concentrated in vacuo to afford 96 mg (0.21 mmol; 67%) of colourlessoil. LC-MS purity (UV/MS): 92/97%, R_(t) 5.45 min, M+1: 352.49. ¹H NMR(400 MHz, CDCl₃): 11.12 (br s), 7.76 (br s), 7.29 (d, 2H, J=8.8Hz), 7.27(d, 4H, J=4.8 Hz), 7.13-7.16 (m, 1H), 6.95 (d, 2H, J=8.8 Hz), 6.16(d,1H, J=4.0 Hz), 2.40-2.48 (m, 1H), 2.18-2.33 (m, 4H), 1.50-1.58 (m, 6H),1.05-1.08 (m, 6H).

Example 102-(2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3-methyl-butyricacid 4-(1-phenyl-cyclohexyl)-phenyl ester

To a stirred mixture at room temperature of PS-carbodiimide (1.2 g; 1.32mmol) and 4-(cyclohexyl-phenyl)methyl-hydroxybenzene (152 mg, 0.60 mmol)in dry THF (2 mL) was added BocValValOH (285 mg, 0.90 mmol) dissolved inTHF (2 mL). After 5 min, DMAP (81 mg; 0.66 mmol) was added and stirringwas continued for 47 h. The reaction mixture was filtered andconcentrated in vacuo and purified by CC using EtOAc (0-25%) in heptaneaffording 297 mg (0.54 mmol; 90%) of colourless oil. LCMS purity(UV/MS): 89/100%, R_(t) 7.61min, M+1: 551.53.

Example 11 2-(2-Amino-3-methyl-butyrylamino)-3-methyl-butyric acid4-(1-phenyl-cyclohexyl)-phenyl ester

To a stirred solution at room temperature of4′-(cyclohexyl)-(phenyl)methyl-1′-(2-tert-butoxycarbonylamino-2-[2-methyl]ethyl)acetoxybenzene(297 mg, 0.54 mmol) in dry DCM (3 mL) was added TFA (300 μL), whichcaused gas evolution. Stirring was continued. After 1 h the reactionmixture was concentrated in vacuo to afford 240 mg (0.43 mmol; 79%) ofcolourless oil as a mixture of isomers. LCMS purity (UV/MS): 100/98%,R_(t) 4.64/4.95min, M+1: 451.56. ¹H NMR (400 MHz, CDCl₃): 8.52 (br s),7.63 (br s), 7.26-7.29 (m, 13H), 7.12-7.16 (m, 1H), 7.06 (d, 1H, J=7.6Hz), 6.95 (d, 1H, J=8.8 Hz), 6.92 (d, 1H, J=8.8 Hz), 4.71-4.74 (m, 1H),4.60-4.63 (m, 1H), 4.17-4.21 (m, 2H), 2.44 (m, 1H), 2.16-2.41 (m, 12H),1.47-1.57 (m, 12H), 0.98-1.05 (m, 24H).

Example 12 2-Iodo-4-(1-phenyl-cyclohexyl)-phenol (ERB-026)

4-(1-Phenyl-cyclohexyl)-phenol (600 mg, 2.38 mmol) was dissolved inacetic acid (10 mL). N-iodosuccinimid (537 mg, 2.38 mmol) was added. Themixture was stirred for 4 h., concentrated and worked-up on thecombiflash (10 g column, 0-10% ethyl acetate in heptane). 718 mg (80%)of the desired product, 90 mg (7.5%) of2,6-diiodo-4-(1-phenyl-cyclohexyl)-phenol and 20 mg (3%) of startingmaterial were isolated.

¹H NMR (400 MHz, CDCl₃): 7.58 (d, 1H, J=2.4 Hz), 7.34-7.24 (m, 4H),7.19-7.14 (m, 1H), 7.12 (dd, 1H, J=2.4 Hz, J=8.6 Hz), 6.88 (d, 1H, J=8.6Hz), 5.18 (br. s, 1H), 2.23-2.15 (m, 4H), 1.62-1.44 (m, 6H).

Example 13 2-Iodo-1-methoxy-4-(1-phenyl-cyclohexyl)-benzene

NaH (60% in mineral oil, 60 mg, 1.50 mmol) was added an ice-cooledsolution of 2-iodo-4-(1-phenyl-cyclohexyl)-phenol (400 mg, 1.06 mmol) inDMF (10 mL). Methyl iodide (125 μL, 2.0 mmol) was added. The reactiontemperature was allowed to reach room temperature. The mixture wasstirred for 2 h, then quenched with water 10 mL and extracted withdichloromethane (2×20 mL). The combined organic phase was dried (Na₂SO₄)and concentrated in vacuo. The residue was taken up in water (20 mL) andextracted with dichloromethane. The organic phase was dried (Na₂SO₄) andconcentrated in vacuo. ¹H-nmr of the syrup (430 mg) indicated fullconversion to the methyl ether. ¹H NMR (400 MHz, CDCl₃): 7.71 (d, 1H,J=2.1 Hz), 7.32-7.25 (m, 4H), 7.18 (dd, 1H, J=2.1 Hz, J=8.8 Hz),7.17-7.13 (m, 1H), 6.72 (d, 1H, J=8.8 Hz), 3.83 (s, 3H), 2.32-2.18 (m,4H), 1.62-1.44 (m, 6H).

Example 14 2-Fluoro-1-methoxy-4-(1-phenyl-cyclohexyl)-benzene

A solution of n-butyl lithium in hexane (1 mL, 1.6 M, 1.6 mmol) wasadded dropwise to a solution of2-iodo-1-methoxy-4-(1-phenyl-cyclohexyl)-benzene (200 mg, 0.51 mmol) andN-fluoro-benzenesulfonimide (320 mg, 1.02 mmol) in dry THF (5 mL) at−78° C. under an argon atmosphere. The mixtures was stirred at −78° C.for 2 h. A GC run after 1 h and 2 h indicated no further conversion ofthe starting material. A saturated solution of NH₄Cl (10 mL) was added.The mixture was extracted with dichloromethane (2×20 mL), the combinedorganic phase was dried (Na₂SO₄) and concentrated in vacuo and worked-upby flash-chromatography. The desired product was isolated in an approx.75% purity according to a ¹H nmr spectrum of the isolated mixture. Themixture was used without further purification in the next reaction.

¹H NMR (400MHz, CDCl₃): 7.32-7.24 (m, 4H), 7.20-7.11 (m, 1H), 7.04-6.95(m, 1H), 7.02-6.94 (m, 2H), 6.89-6.84 (m, 1H), 3.85 (s, 3H), 2.32-2.18(m, 4H), 1.61-1.50 (m, 6H).

Example 15 2-Fluoro-4-(1-phenyl-cyclohexyl)-phenol (ERB-006)

A solution of the crude2-fluoro-1-methoxy-4-(1-phenyl-cyclohexyl)-benzene in dichloromethane(100 mg, 0.25 mmol, 2 mL) was added to a solution of borane tribromidein dichloromethane (1 M, 0.25 ml, 025 mmol) at −78° C. under an argonatmosphere and stirred at r.t for 3 h. Water (10 mL) was added and themixture was extracted with dichloromethane (2×10 mL). The combinedorganic phase was dried (Na₂SO₄) and concentrated to a syrup. Work-up byflash-chromatography (eluent: 30→80% dichloromethane in heptane) gavethe title product in a yield of 50 mg.

LC-MS purity (UV/MS): 100/100%, R_(t) 5.15/5.19 min, M−1: 269.6. ¹H NMR7.31-7.24 (m, 5H), 7.17-7.12 (m, 1H), 6.96 (ddd, 1H, J=2.0 Hz, J=12.9Hz, J=14.7 Hz.), 6.91 (dd, 1H, J=8.4 Hz, J=17.1 Hz), 4.98 (br. s, 1H),2.28-2.18 (m, 4H), 1.61-1.48 (m, 6H).

Example 16 1-Methoxy-4-(1-phenyl-cyclohexyl)-benzene, procedure A

A mixture of AuCl₃ (7.6 mg, 0.025 mmol) and AgOTf (19.3 mg, 0.075 mmol)was stirred in dichloromethane (2 mL) for 30 min. Anisole (54 mg, 0.5mmol) and 1-Phenyl-1-cyclohexene (158 mg, 1 mmol) were then addedsequentially. The resulting mixture was stirred at room temperatureovernight. Evaporation of the solvent under reduced pressure gave 130 mgof crude material. Flash chromatography (heptane:ethyl acetate 95:5)afforded 90 mg of a as a colorless oil. R_(f)=0.33 (heptane:ethylacetate 95:5). ¹H-NMR (400 MHz, CDCl₃) δ 7.27-7.25 (m, 4H), 7.19 (d, 2H,J=8.8 Hz), 7.12 (m, 1H), 6.81 (d, 2H, J=8.8 Hz), 3.77 (s, 3H), 2.30-2.20(m, 4H), 1.62-1.44 (m, 6H). ¹³C-NMR (100 MHz, CDCl₃) δ 157.4, 149.2,140.9, 128.4 (two carbons), 128.4 (two carbons), 127.3 (two carbons),125.5, 113.8 (two carbons), 55.4, 45.9, 37.5 (two carbons), 26.7, 23.2(two carbons).

Example 17 1-Methoxy-4-(1-phenyl-cyclohexyl)-benzene (B), procedure B

4-(1-phenylcyclohexyl)phenol (20 mg, 0.08 mmol) was dissolved in DMF (2mL). A suspension of NaH in oil (60%, 5 mg, 0.125 mmol) was added. Afterstirring for 5 minutes methyl iodide (0.05 mL; 0.8 mmol) was added. Thereaction mixture was stirred for 2 h. (tlc indicated full conversion ofthe starting material) then quenched with water (10 mL). Dichloromethane(10 mL) was added. The mixture was shaken and the organic phaseseparated off, dried (Na₂SO₄) and concentrated to syrup. The titleproduct was afforded after work-up by flash-chromatography (eluentdichloromethane). Yield: 20 mg, quantitatively. LC-MS purity (UV/MS):100/-, R_(t) 6.48 min. ¹H NMR data were in accordance with the datawritten above.

Example 18 Acetic acid 4-(1-phenyl-cyclohexyl)-phenyl ester

4-(1-phenylcyclohexyl)phenol (100 mg, 0.40 mmol) was dissolved indichloromethane (5 mL). Pyridine (1 mL) and the acylating reagent wereadded (1.60 mmol, 5 equiv.). The reaction mixture was stirred for 2 h.at room temperature (tlc indicated full conversion of the startingmaterial) then quenched with water (10 mL). Dichloromethane (10 mL) wasadded. The mixture was shaken and the organic phase separated off, dried(Na2SO₄) and concentrated to syrup. The acylated product was affordedafter flushing the product through a block of silica (eluentdichloromethane) Yield 120 mg, isolated as a crystalline product. ¹H-NMR(400 MHz, CDCl₃) d 7.30-7.24 (m, 6H), 7.17-7.10 (m, 1H), 7.01-6.96 (m,2H), 2.36-2.19 (m, 7H), 1.62-1.45 (m, 6H).

Example 19 2,2-Dimethyl-propionic acid 4-(1-phenyl-cyclohexyl)-phenylester

4-(1-phenylcyclohexyl)phenol (100 mg, 0.40 mmol) was dissolved indichloromethane (5 mL). Pyridine (1 mL) and the acylating reagent wereadded (1.60 mmol, 5 equiv.). The reaction mixture was stirred for 2 h.at room temperature (tlc indicated full conversion of the startingmaterial) then quenched with water (10 mL). Dichloromethane (10 mL) wasadded. The mixture was shaken and the organic phase separated off, dried(Na₂SO₄) and concentrated to syrup. The acylated product was affordedafter flushing the product through a block of silica (eluentdichloromethane) Yield: 110 mg, isolated as crystalline product ¹H-NMR(400 MHz, CDCl₃) d 7.29-7.23 (m, 6H), 7.16-7.10 (m, 1H), 6.98-6.93 (m,2H), 2.34-2.20 (m, 4H), 1.61-1.45 (m, 6H), 1.33 (s, 9H).

Example 20 Dimethyl-sulfamic acid 4-(1-phenyl-cyclohexyl)-phenyl ester

DMAP (20 mg, 0.16 mmol) and dimethylcarbamoylchloride (568 mg, 4.0 mmol)was added sequentially to a mixture of 4-(1-phenylcyclohexyl)phenol (200mg, 0.79 mmol) and Et₃N (400 mg, 4.0 mmol) in CH₂Cl₂ (10 mL). Theresulting mixture was stirred at room temperature overnight. Thesolution was further washed with 2M HCL (aq) (20 mL), water (20 mL),saturated NaHCO₃ (20 mL) and water (20 mL) and dried over Na₂SO₄.Evaporation of the solvent under reduced pressure gave 180 mg of crudematerial. Flash chromatography (heptane:ethyl acetate 95:5) afforded 120mg (42%) of a as a slightly yellowish oil. R_(f)=0.21 (heptane:ethylacetate 90:10). ¹H-NMR (400 MHz, CDCl₃) δ 7.30-7.12 (m, 7H), 7.17 (d,2H, J=9.2 Hz), 2.94(s, 6H), 2.34-2.18 (m, 4H), 1.66-1.44 (m, 6H).¹³C-NMR (100 MHz, CDCl₃) δ 148.2, 148.0, 147.7, 128,8 (two carbons),128.5 (two carbons), 127.4 (two carbons), 125.8, 121.4 (two carbons),46.3, 39.0 (two carbons), 37.4 (two carbons), 26.5, 23.0 (two carbons).

Example 21 Phosphoric acid dibenzyl ester 4-(1-phenyl-cyclohexyl)-phenylester

1H-tetrazole (6 g of a 3% solution in CH₃CN, 2.6 mmol) was added to astirred solution of 4-(1-phenylcyclohexyl)phenol (200 mg, 0.79 mmol) anddibenzyl-N,N-diisopropyl phosphoramidite (575 mg, 1.7 mmol) in CH₂Cl₂(10 mL). After 30 min, the mixture was cooled to 0° C. and m-CPBA (570mg, 2.3 mmol, 70%) was added. The mixture was stirred for 40 min, washedwith 10% aqueous Na₂S₂O₃ and NaHCO₃ (saturated), dried over Na₂SO₄,filtered and the solvent was evaporated under reduced pressure. Flashchromatography (heptane:ethyl acetate 80:20) afforded 90 mg of a as acolorless oil. R_(f)=0.58 (heptane:ethyl acetate 50:50). ¹H-NMR (400MHz, CDCl₃) δ 7.34-7.10 (m, 15H), 7.19 (d, 2H, J=8.8 Hz), 7.04 (d, 2H,J=8.8 Hz), 5.04 (d, 2H, J=8.4 Hz), 5.04 (d, 2H, J=8.4 Hz), 2.32-2.18 (m,4H), 1.60-1.46 (m, 6H). ¹³C-NMR (100 MHz, CDCl₃) δ 151.6, 148.4 (d, J=15Hz), 145.7, 135.8 (two carbons, d, J=8.6 Hz), 128.8 (two carbons), 128.8(four carbons), 128.7 (two carbons), 128.5 (two carbons), 128.2 (fourcarbons), 127.3 (two carbons), 125.7, 119.8 (two carbons, d, J=4.9 Hz),70.1 (two carbons, d, J=5.7 Hz), 46.1, 37.4 (two carbons), 26.5, 23.1(two carbons).

Example 22 Phosphoric acid mono-[4-(1-phenyl-cyclohexyl)-phenyl]ester

A mixture of phosphoric acid dibenzyl ester4-(1-phenyl-cyclohexyl)-phenyl ester (133 mg, 2.6 mmol) and 10%palladium on carbon (100 mg) in EtOAc (10 mL) was stirred under H₂ (oneatmosphere) for two hours. The mixture was filtered through a pad ofCelite, and the solvent was evaporated under reduced pressure to yield79 mg (92%) of a colourless semisolid. R_(f)=0.22 (CHCl₃:MeOH:H₂O65:25:4). ¹H-NMR (400 MHz, CDCl₃) δ 7.40-6.90 (m, 9H), 2.30-2.00 (m,4H), 1.60-1.30 (m, 6H).

Example 23 (4-Benzyloxy-phenyl)-phenyl-methanone

NaH (60% in mineral oil, 1.2 g, 30 mmol) was added to an ice-cooledsolution of (4-hydroxy-phenyl)-phenyl-methanone (5 g, 25.2 mmol) in DMF(25 mL). Stirred for 20 minutes at room temperature. Benzyl bromide (6.1ml, 50 mmol) was added at 0° C. The reaction temperature was raised toroom temperature after 1 h. Stirred 2 h. Water (20 mL) was added andaqueous phase was extracted dichloromethane (2×30 mL). The combinedorganic phase was concentrated and purified by flash chromatography(eluent: dichloromethane). ¹H nmr revealed the product was pure. Yield:7.0 g, 96%

¹H NMR (400 MHz, CDCl₃): 7.83 (d, 2H, J=8.4 Hz), 7.77 (d, 2H, J=7.2 Hz),7.58-7.52 (m, 1H), 7.50-7.32 (m, 6H), 7.03 (d, J=8.4 Hz), 5.17 (s, 2H).

Example 24 1-(1-Allyloxy-1-phenyl-but-3-enyl)-4-benzyloxy-benzene

A solution of allylmagnesium bromide in diethyl ether (1 M, 15 ml) wasadded to an ice water cooled solution of the(4-benzyloxy-phenyl)-phenyl-methanone (4.0 g, 13.87 mol) in THF (20 mL).The mixture was stirred for 1 h at r.t, and then quenched with water (20mL). The aqueous phase was extracted with dichloromethane (2×30 ml). Thecombined organic phase was dried (Na₂SO₄) and concentrated to syrup. Thecrude was dissolved in DMF (10 mL) cooled in an ice-water bath. NaH (600mg, appr. 15 mmol) was added and the mixture was stirred for ½ h.Allylbromide (1.25 mL, 15.0 mmol) was added and the mixture was stirredat 40° C. for 1 h. Water (20 mL) was added and aqueous phase wasextracted dichloromethane (2×30 mL). The combined organic phase wasconcentrated. Purification using the combiflash (10 g, column, 0-10ethyl acetate in heptane) gave the diene in an yield of 4.2 g (81%).

¹H NMR (400 MHz, CDCl₃): 7.53-7.26 (m, 12H), 6.98 (d, 2H, J=8.6 Hz),6.05-5.94 (m, 1H), 5.78-5.65 (m, 1H), 5.47-5.39 (m, 1H), 5.24-5.03 (m,5H), 3.84-3.80 (m, 2H), 3.22-3.17 (m, 2H).

Example 25 2-(4-Benzyloxy-phenyl)-2-phenyl-3,6-dihydro-2H-pyran

1-(1-Allyloxy-1-phenyl-but-3-enyl)-4-benzyloxy-benzene (4.2 g, 10.1mmol) was dissolved in dichloromethane (50 mL) andbis(tricyclohexylphosphine)benzylidene ruthenium (IV) dichloride (25 mg,0.03 mmol) was added. Stirred at r.t. for 1 h. TLC indicated fullconversion of the starting material. A solution of methylamine in THF (1M, 1 mL) was added. The solution was eluted through a block of silica.The silica was washed with a solution of dichloromethane and ethylacetate (1:1, 100 mL). The combined organic phase was concentrated toslightly coloured syrup (4.1 g, quantitatively).

¹H NMR (400 MHz, CDCl₃): 7.49-7.24 (m, 12H), 6.95 (d, 2H, J=8.8 Hz),6.05-5.98 (m, 1H), 5.72-5.65 (m, 1H), 4.16-4.00 (m, 2H), 2.90-2.76 (m,2H).

Example 26 4-(2-Phenyl-tetrahydro-pyran-2-yl)-phenol

2-(4-Benzyloxy-phenyl)-2-phenyl-3,6-dihydro-2H-pyran (4.1 g) wasdissolved in methanol (25 mL) and ethyl acetate (5 mL). 5% Palladium oncarbon (10 mg) was added. Nitrogen was bubbled through the solution.Ammonium acetate (4 g) was added. The mixture was stirred for 6 h,filtered through a block of celite and concentrated to a solid. NMRindicated full conversion to the title product (3.1 g, 12.2 mmol).

¹H NMR (400 MHz, CDCl₃): 7.39-7.16 (m, 7H), 6.78-6.73 (m, 2H), 3.71 (t,2H, J=5.4 Hz), 2.26 (ddd, 2H, J=2.6 Hz, J=5.4 Hz, 9.2 Hz), 1.76-1.70(2H, m), 1.64-1.57 (m, 2H).

Example 27 Acetic acid 4-(2-phenyl-tetrahydro-pyran-2-yl)-phenyl ester

4-(2-Phenyl-tetrahydro-pyran-2-yl)-phenol (500 mg, 2 mmol) was dissolvedin pyridine (10 mL). Acetic anhydride (1 mL) was added at drop wise at0° C. The reaction temperature was allowed to raise to room temperature.After 1 h the reaction was quenched the addition of water (5 mL).Dichloromethane (20 mL) was added. The organic phase was washed withaqueous HCl (1M, 2×10 mL), brine (10 mL), dried (Na₂SO₄) andconcentrated in vacuo. Purified on a short column (eluent:dichloromethane). Yield: 560 mg.

¹H NMR (400 MHz, CDCl₃): 7.39-7.66 (m, 2H), 7.32-7.19 (m, 5H), 7.02-7.00(m, 2H), 3.73-3.69 (m, 2H), 2.25 (s, 3H), 1.73 (t, 2H, J=6 Hz),1.65-1.57 (2H, m), 1.30-1.25 (m, 2H).

Example 28 Enzymatic Resolution

Acetic acid 4-(2-phenyl-tetrahydro-pyran-2-yl)-phenyl ester (50 mg, 0.17mmol) was dissolved in a mixture of isopropylether (0.5 mL) and THF (0.2mL). Phosphate buffer (100 mmol, pH=7, 2 mL) and Amono Lipase AK, fromPseudomonas Fluorescens (50 mg) were added. Stirred at room temperaturefor 2 h. The mixture was filtered, dichloromethane (10 mL) was added.The organic phase was washed with water (10 mL), dried (Na₂SO₄) andconcentrated in vacuo. Chiral LC-MS indicated that4-(2-phenyl-tetrahydro-pyran-2-yl)-phenol was formed in an ee of 71%,the absolute configuration of the enantiomer was not determined.

Example 29 4-Phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid9H-fluoren-9-ylmethyl ester

4-Phenyl-1,2,3,6-tetrahydropyridine (200 mg, 1.26 mmol) was dissolved indry acetonitrile (5 mL) and cooled in ice-water bath.N-(9-Fluoroenylmethoxycarbonyloxy)-succinimide (475 mg, 1.4 mmol) wasadded. Stirred over night at room temperature. TLC indicated fullconversion of the starting material. An aqueous solution of saturatedNaHCO₃ (5 mL) was added and the mixture was extracted withdichloromethane (2×20 mL). The combined organic phase was dried (Na₂SO₄)and concentrated in vacuo. The product was isolated after columnchromatography (gradient dichloromethane→ethylacetate). Yield: 390 mg.The product was pure according to ¹H nmr.

¹H NMR (400 MHz, CDCl₃): 7.79 (d, 2H, J=7.4 Hz), 7.63 (d, 2H, J=7.4 Hz),7.44-7.25 (m, 9H), 6.07 (br. s, 1H), 4.49 (d, 2H, J=6.9 Hz), 4.30 (t,1H, J=6.9 Hz), 4.16 (br. s, 2H), 3.72 (br. s, 2H), 2.55 (br. s, 2H).

Example 30 4-(4-Hydroxy-phenyl)-4-phenyl-piperidine-1-carboxylic acid9H-fluoren-9-ylmethyl ester

4-Phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid 9H-fluoren-9-ylmethylester (200 mg, 0.52 mmol) was treated with a drop of BF₃*H₃PO₄ andphenol (200 mg, 2.1 mmol) at 60° C. for 6 h. Water (10 mL) was added andaqueous phase was extracted dichloromethane (2×10 mL). The combinedorganic phase was concentrated. ¹H nmr indicated full conversion of thestarting material. The desired product was isolated after flashchromatography. Yield: 270 mg. LC/MS purity (UV/MS): 96/91%, R_(t) 7.32min. M+1: 432.

¹H NMR (400 MHz, CDCl₃): 7.76 (d, 2H, J=7.2 Hz), 7.58 (d, 2H, J=7.2 Hz),7.42-7.15 (m, 9H), 7.13-7.08 (m, 2H), 6.80-6.75 (m, 2H), 4.45 (d, 2H,J=6.7 Hz), 4.23 (t, 1H, J=6.7 Hz), 3.52 (br. s, 4H), 2.30 (br. s., 4H).

Example 31 4-(4-Phenyl-piperidin-4-yl)-phenol

4-(4-Hydroxy-phenyl)-4-phenyl-piperidine-1-carboxylic acid9H-fluoren-9-ylmethyl ester (270 mg, 0.57 mmol) was treated with asolution of piperidine in DMF (20%, 5 mL) for 2 h. TLC indicated fullconversion of the starting material. Concentrated in vacuo to a solid.Worked-up by flash chromatography. LC-MS indicated formation of acomplex mixture. The title product was isolated in an analytical amount.LC/MS purity (UV/MS): 90/90%, R_(t) 3.15 min. M+1: 254

¹H NMR (400 MHz, CD₃OD): 7.30-7.29 (m, 4H), 7.19-7.13 (m, 3H), 6.78-6.74(m, 2H), 4.58 (br s, 3 H), 3.21 (t, 4H, J=5.8 Hz), 2.66-2.62 (m, 4H).

Example 32 4-(4-Phenyl-tetrahydro-pyran-4-yl)-phenol

4-Phenyl-tetrahydro-pyram-4-ol (20 mg) and phenol (100 mg) were meltedand FeCl₃ (few crystals) was added. The mixture was stirred at 50° C.for ½ h. GC-MS indicated full conversion to the desired compound. TLCrevealed formation of a compound with an R_(f) value just below phenol(eluent: dichloromethane Phenol, R_(f)=0.28, product, R_(f)=0.26).

Dichloromethane (10 mL) was added. The organic phase was washed withwater (10 mL), dried (Na₂SO₄) and concentrated in vacuo. Purified byflash chromatography (eluent 5% ethyl acetate in dichloromethane? 25%ethyl acetate in dichloromethane). Yield: 32 mg. LC/MS purity (UV/MS):100/100%, R_(t) 2.98 min. M−1: 253

¹H NMR (400 MHz, CD₃OD): 7.29-7.22 (m, 4H), 7.14-7.07 (m, 3H), 6.72-6.67(m, 2H), 3.71 (br. t., 4H, J=5.4 Hz), 2.39 (br. t., 4H, J=5.4 Hz).

Example 33 2-(1-Phenyl-cyclohexyl)-thiophene

Phenyl cyclohexene (50 mg) and thiophene (100 mg) were dissolved in 33%HBr in acetic acid (0.5 mL). The mixture was stirred at room temperatureover night. Tlc indicated full conversion of the starting material.Dichloromethane (10 mL) was added. The organic phase was washed withsaturated NaHCO₃ (3×10 mL), dried Na₂SO₄ and concentrated in vacuo. Thedesired product was afforded after flash chromatography (eluent:dichloromethane). Yield: 39 mg. LC/MS purity (UV/MS): 100/90%, R_(t)6.22 min. M+1: 243

¹H NMR (400 MHz, CD₃Cl): 7.29-7.17 (m, 4H), 7.12-7.07 (m, 1H), 7.06 (dd,1H, J=5.0 Hz, J=1.0 Hz), 6.83 (dd, 1H, J=5.0 Hz, J=3.5 Hz, 1H), 6.71(dd, J=3.5 Hz, J=1.0 Hz, 1H), 2.35-2.24 (m, 4H), 1.62-1.35 (m, 6H).

Example 34 4-(1-Pyridin-3-yl-cyclohexyl)-phenol

The pyridine-boronic acid (1 g, 8.1 mmol),1-cyclohexenyl-1-trifluoromethanesulfonate the triflate (2 g, 8.1 mmol)(TLC indicated that the triflate was partly decomposed (estimated purity30%)) and potassium fluoride (200 mg) were suspended in dioxane. Argonwas bubbled through the mixture. The palladium catalyst (50 mg) wasadded and the reaction mixture was stirred at 100° C. for 20 h. Themixture was stirred at 100° C. for 1 day. Dichloromethane (20 mL) andaqueous HCl (1 n, 20 mL) were added. The organic phase was separatedoff. The aqueous phase was neutralised with saturated NaHCO₃ (pH 7-8)and extracted with dichloromethane (2×30 mL). The combined organic phasewas dried (Na₂SO₄) and concentrated in vacuo. The desired product wasobtained after purification with flash chromatography. Yield: 150 mgsyrup.

The syrup (75 mg) was dissolved in phenol (200 mg). Triflic acid (1drop) was added. Stirred at 80° C. over night. The desired product wasafforded after purification by flash chromatography. Yield: 25 mg. LC/MSpurity (UV/MS): 100/100%, R_(t) 3.20 min. M+1: 254

¹H NMR (400 MHz, CD₃Cl): 8.49 (d, J=2.2 Hz, 1H), 8.36 (dd, J=4.9 Hz,J=1.5 Hz, 1H), 7.62 (ddd, 1H, J=8.0 Hz, J=2.2 Hz, J=1.5 Hz), 7.24 (dd,1H, J=8.0 Hz, J=4.9 Hz, 1H), 7.10-7.06 (m, 2H), 6.76-6.72 (m, 2H),2.33-2.16 (m, 4H), 1.64-1.46 (m, 6H).

Example 35 1-(4-Hydroxy-phenyl)-cyclohexanecarbonitrile

1-(4-Methoxyphenyl)-1-cyclohexanexanecarbonitrile (100 mg, 0.46 mmol)was dissolved in dichloromethane (5 mL) and a solution of borontribromide in dichloromethane (1M; 0.5 mmol, 0.5 mL) was added dropwice.Stirred at room temperature for 1 h, concentrated. ¹H nmr the reactionhad proceeded 20%. The syrup was dissolved in dichloromethane and asolution of boron tribromide in dichloromethane (1 mL, 1.0 mmol) wasadded. The solution was stirred for 24 h, concentrated and worked-up byflash chromatography. Yield: 82 mg. LC/MS purity (UV/MS): 100/90%, R_(t)6.0 min. M−1: 200

¹H NMR (400 MHz, CD₃Cl): 7.34-7.29 (m, 2H), 6.87-6.83 (m, 2H), 2.16-2.10(m, 2H), 1.90-1.66 (m, 8H).

Example 36 Thiophene-3-yl cyclohexene

3-Thiophene boronic acid (128 mg, 1.00 mmol), cyclohexenyl triflate(230.2 mg, 1.00 mmol) was dissolved in Et₂O (4 mL) and 2M Na₂CO₃ (1 mL).The mixture was degassed and Pd(PPh₃)₄ (0.05 mmol) added. After stirringat room temperature for 4 h the mixture was filtered through celite,rinsed with Et₂O, dried (Na₂SO₄) and subjected to column chromatography(silica, pentane) to yield 150 mg of a volatile liquid. GC-MS: M⁺=164.

¹H-NMR (400 MHz, CDCl₃): 7.26-7.23 (m, 2H), 7.09-7.07 (m, 1H), 6.19-6.17(m, 1H), 2.43-2.38 (m, 2H), 2.22-2.18 (m, 2H), 1.81-1.75 (m, 2H),1.69-1.63 (m, 2H). ¹³C-NMR (125 MHz, CDCl₃): 144.3, 132.1, 125.4, 124.9,124.1, 118.0, 27.5, 25.8, 23.1, 22.5.

Example 37 1-(4-Hydroxyphenyl)-thiophene-3-yl cyclohexane

Thiophene-3-yl cyclohexene (72.3 mg, 0.44 mmol), and phenol (82.8 mg,0.88 mmol) was mixed and gently heated until uniform and BF₃*H₃PO₄ (4uL, 0.044 mmol) was added. The mixture was heated at 70° C. overnightand the dark residue was diluted with EtOAc, washed with sat. NaHCO₃,dried and concentrated. Column chromatography (silica, 0-20% EtOAc) gavea mixture of isomers and the desired product could be isolated bypreparative TLC (DCM eluent). Yield: 3.7 mg, off-white/pale yellowsolid. GC-MS: M⁺=258.

¹H-NMR (400 MHz, CDCl₃): 7.20 (dd, J=5.08 Hz, 2.93 Hz, 1H), 7.13 (d,J=8.80 Hz, 2H), 6.92 (dd, J=2.93 Hz, 1.37 Hz, 1H), 6.87 (dd, J=5.08 Hz,1.37 Hz, 1H), 6.74 (d, J=8.80 Hz, 2H), 2.21-2.17 (m, 4H), 1.57-1.44 (m,6H).

Example 38 Receptor Selection and Amplification Technology Assay

The functional receptor assay, Receptor Selection and AmplificationTechnology (R-SAT™), was used with minor modifications from theprocedure described in U.S. Pat. No. 5,707,798, which is herebyincorporated by reference in its entirety, to screen compounds forefficacy at the Estrogen receptors alpha and beta (ERα, ERβ). NIH3T3cells were grown in roller bottles to 70-80% confluence. Cells were thentransfected for 12-16 h with plasmid DNAs using Polyfect (Qiagen Inc.)as per the manufacturer's protocol. R-SAT assays were typicallyperformed by transfecting 30 ug/bottle of receptor and 50 ug/bottle ofβ-galactosidase plasmid DNA. All receptor and helper constructs usedwere in mammalian expression vectors. Helpers are defined as signalingmolecules that modulate both ligand-dependent and/or ligand-independentfunction of the ER receptors, typically co-activators and kinases.NIH3T3 cells were transfected for 12-16 h, then trypsinized and frozenin DMSO. Frozen cells were later thawed, plated at 10,000-40,000 cellsper well of a 96 well plate containing 4-(1-Phenyl-cyclohexyl)-phenol.Cells were then grown in a humidified atmosphere with 5% ambient CO₂ forfive days. Media was then removed from the plates and marker geneactivity was measured by the addition of the β-galactosidase substrateo-nitrophenyl β-D-galactopyranoside (ONPG, in PBS with 5% NP-40). Theresulting colorimetric reaction was measured in a spectrophotometricplate reader (Titertek Inc.) at 420 nM. All data were analyzed using thecomputer program XLFit (IDBSm).

These experiments provided a molecular profile, or fingerprint, for eachagent tested at the human Estrogen receptors. As can be seen in Table 1and FIG. 1, 4-(1-Phenyl-cyclohexyl)-phenol (ERB-002) selectivelyactivates Estrogen beta receptor (ERβ) relative to the Estrogen alphareceptor (ERα).

TABLE 1 pEC₅₀ % Efficacy pEC₅₀ % Efficacy Compound ERα ERα ERβ ERβERB-002 5.5 50 7.2 85 ERB-004 5.5 77 7.5 90 ERB-005 5.4 48 7.2 63ERB-007 5.8 30 7.1 57 ERB-009 5.4 100 7.2 138 ERB-011 <5.0 20 7.1 37ERB-012 6.2 69 6.9 41 ERB-014 5.9 120 7.1 87 ERB-017 6.6 80 8.2 46ERB-030 5.6 95 7.2 46 ERB-031 5.6 124 6.1 62 ERB-037 5.8 114 8.1 48ERB-043 <5.0 13 7.0 25Efficacy is relative to the reference ligand Estrone.

Example 39 CFA Induced Arthritis Rat Model Assay

Naïve, male Sprague-Dawley rats (225-250 g; n=6 per group) served assubjects. Response latencies to a noxious thermal stimulus were measuredusing the 52° C. hot plate test. After obtaining baseline responses, 0.1ml of Freund's complete adjuvant (CFA) or vehicle (inactivated CFA(iCFA)) was injected into the dorsal surface of the left hind paw.Response latencies were again measured 4 days following CFA (or iCFA)administration, a time point when thermal hyperalgesia is stable. Asignificant decrease in the hot plate latency was interpreted as thepresence of thermal hyperalgesia. Following testing, thickness of bothhind paws were measured (using a micrometer) in order to quantifypossible edema formation at the injection site. Various doses of4-(1-Phenyl-cyclohexyl)-phenol (ERB-002) (1.0, 3.0 or 10 mg/kg) orvehicle (DMSO) were administered (s.c.) following testing on Day 4, andthen daily following testing for a period of 3 days. FIG. 2 illustratesthe dose dependent reversal of thermal hyperalgesia in this model. FIG.3 illustrates the dose dependent reversal of edema in this model.

Example 40 Uterotrophic In Vivo Assay

The effect of ERB-002 on uterine weight was assessed based on thepreviously published method of Harris et al., Endocrin, 2003, 143:4172,which is hereby incorporated by reference in its entirety. Naive, femaleSprague-Dawley rats (30-40 g; n=6 per group) served as subjects. Ratsreceived daily subcutaneous injections of vehicle (100% DMSO), PPT (1.0mg/rat)), a reportedly selective ERα agonist (Stauffer, 2000, J Med Chem43:4934) or various doses of ERB-002 (10, 30 or 100 mg/kg) for a totalof 3 days. Approximately 24 hours after the final injection, the ratswere sacrificed, the uteri removed, trimmed of adhesions, fluid expelledand then weighed. Uterine weight was normalized as a percentage of totalbody weight by the following formula: % TBW=[(uterus weight (inmg)/1000)/(body weight (in g))]*100. FIG. 4 illustrates that ERB-002does not display uterotrophic properties in vivo in immature femalerats.

1. A compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein: n is an integerselected from the group consisting of 1, 2, 3, 4, 5 and 6; R₁ isselected from the group consisting of hydrogen, C₁-C₈ straight chainedor branched alkyl, C₁-C₈ straight chained or branched alkenyl,cycloalkyl, cykloalkenyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroalicyclyl, sulfonyl, C₁-C₈ straight chained or branchedperhaloalkyl, —C(═Z)R₅, —C(═Z)OR₅, —C(═Z)N(R₅)₂, —S(═O)₂NR_(5a)R_(5b),—P(═O)(OR₅)₂, and —CH₂OC(═O)R₅; R₂, R_(2a), R_(2b), R_(2c), and each R₆are separately selected from the group consisting of hydrogen, alkyl,alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheteroalicyclyl, hydroxy, halogen, sulfonyl, perhaloalkyl, —CN, —OR₅,—NR₅R_(5a), —NR₅NR_(5a)R_(5b), —NR₅N═CR_(5a)R_(5b),—N(R₅)C(R_(5a))═NR_(5b), —C(═Z)R₅, —C(═Z)OR₅, —C(═Z)NR₅R_(5a),—N(R₅)—C(═Z)R_(5a), —N(R₅)—C(═Z)NR_(5b)R_(5a), —OC(═Z)R₅,—N(R₅)—S(═O)₂R_(5a), and —SR₅; each Y is separately selected from thegroup consisting of methylene, methylene substituted with one or two R₆groups, sulfur, oxygen, C═O, unsubstituted nitrogen, and nitrogensubstituted with a substituent selected from the group consisting ofhydrogen, unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, andsubstituted or unsubstituted heteroalicyclyl, wherein the alkyl, whensubstituted, is not substituted with phenyl, provided that the ringdefined by the Y groups is not a 4-substituted piperidine, and providedthat when the ring defined by the Y groups is 2,6-dioxane, whereposition 1 of the dioxane is the position to which the A group isattached, then A is a substituted aryl, and provided that when one Y isoxygen, a second Y is C═O, and a third Y is nitrogen, then thecombination of oxygen, C═O, and nitrogen forms an oxazinanone two Ygroups are optionally bound together to form a substituted orunsubstituted C₁-C₉ cycloalkyl or C₁-C₉ heteroalicyclyl; R_(2a) isoptionally bound to one Y group to form a substituted or unsubstitutedC₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or C₄-C₉ cycloalkenyl; any bondrepresented by a dashed and solid line represents a bond selected fromthe group consisting of a single bond and a double bond; A is selectedfrom the group consisting of substituted heteroaryl, unsubstitutedheteroaryl, substituted heteroalicyclyl, unsubstituted heteroalicyclyl,unsubstitued aryl, and substituted aryl, wherein the heteroaryl isselected from the group consisting of furan, thiophene, phthalazinone,pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole,triazole, thiadiazole, pyran, pyridine, pyridazine, pyrimidine, andpyrazine; A is optionally bound to one Y group to form a substituted orunsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or C₄-C₉cycloalkenyl; Z is oxygen or sulfur; and each R₅, R_(5a) and R_(5b) areseparately selected from the group consisting of hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, andsubstituted or unsubstituted heteroalicyclyl; provided that when every Yis a substituted or unsubstituted methylene, then A is not a substitutedor unsubstituted aryl; and provided that A and the ring defined by the Ygroups and the carbon atom to which they are attached are not bothsimultaneously carbocyclic rings or heterocyclic rings.
 2. The compoundof claim 1, wherein: n is an integer selected from the group consistingof 3, 4, and 5; R₁ is selected from the group consisting of hydrogen,C₁-C₄ straight chained or branched alkyl, C₁-C₄ straight chained orbranched alkenyl, C₁-C₄ straight chained or branched perhaloalkyl, andsubstituted or unsubstituted aryl; R₂, R_(2a), R_(2b), R_(2c) areseparately selected from the group consisting of hydrogen, C₁-C₅straight chained or branched alkyl, C₁-C₅ alkenyl, hydroxy, halogen,sulfonyl, perhaloalkyl, —CN, —OR₅, —C(═O)R₅, —C(═O)OR₅, —C(═O)NR₅R_(5a),—N(R₅)—C(═O)R_(5a), —N(R₅)—S(═O)₂R_(5a), —OC(═O)R₅, and —SR₅; each Y isseparately selected from the group consisting of substituted orunsubstituted methylene, sulfur, oxygen, substituted or unsubstitutednitrogen or C═O; and A is selected from the group consisting ofsubstituted heteroaryl, unsubstituted heteroaryl, unsubstitued aryl, andsubstituted aryl that is unsubstituted at the para position.
 3. Thecompound of claim 1, wherein: n is 3; R₁ is selected from the groupconsisting of hydrogen, C₁-C₅ straight chained or branched alkyl,substituted or unsubstituted aryl; R₂, R_(2a), R_(2b), R_(2c) areseparately selected from the group consisting of hydrogen, C₁-C₅straight chained or branched alkyl, F, Cl, Br, perhaloalkyl, —CN, —OR₅,—C(═O), and —SR₅; each Y is separately selected from the groupconsisting of substituted or unsubstituted methylene, oxygen,substituted or unsubstituted nitrogen, or C═O; and A is selected fromthe group consisting of substituted heteroaryl, unsubstitutedheteroaryl, unsubstitued aryl, and substituted aryl that isunsubstituted at the para position.
 4. The compound of claim 1, selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, wherein n is
 3. 6. The compound of claim 1, wherein R₁ is hydrogen.7. The compound of claim 1, wherein at least one Y is oxygen.
 8. Thecompound of claim 7, wherein each additional Y is separately selectedfrom the group consisting of methylene, methylene substituted with oneor two R₆ groups, unsubstituted nitrogen, and C═O.
 9. The compound ofclaim 7, wherein each additional Y is separately selected from the groupconsisting of methylene, methylene substituted with one or two R₆groups, unsubstituted nitrogen, and C═O, wherein each R₆ isindependently selected from the group consisting of hydrogen, alkyl,alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheteroalicyclyl, hydroxy, halogen, sulfonyl, perhaloalkyl, —CN, —OR₅,—NR₅R_(5a), —NR₅NR_(5a)R_(5b), —NR₅N═CR_(5a)R_(5b),—N(R₅)C(R_(5a))═NR_(5b), —C(═Z)R₅, —C(═Z)OR₅, —C(═Z)NR₅R_(5a),—N(R₅)—C(═Z)R_(5a), —N(R₅)—C(═Z)NR_(5b)R_(5a), —OC(═Z)R₅,—N(R₅)—S(═O)₂R_(5a), and —SR₅.
 10. The compound of claim 7, wherein eachadditional Y is separately selected from the group consisting ofmethylene, methylene substituted with one or two R₆ groups,unsubstituted nitrogen, and C═O, wherein each R₆ is independentlyselected from the group consisting of hydrogen, alkyl, alkenyl,cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstitutedheteroalicyclyl, hydroxy, halogen,—OR₅, and —NR₅R_(5a).
 11. The compoundof claim 7, wherein each additional Y is separately selected from thegroup consisting of methylene, methylene substituted with one or two R₆groups, unsubstituted nitrogen, and C═O, wherein each R₆ isindependently hydrogen or alkyl.
 12. The compound of claim 1, wherein Ais substituted aryl that is unsubstituted at the para position.
 13. Thecompound of claim 1, wherein A is substituted with alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxyl,alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, silyl,trihalomethanesulfonyl, and amino, including mono- and di-substitutedamino groups.
 14. The compound of claim 1, wherein A is substituted withhalo.
 15. The compound of claim 14, wherein the halo is fluoro.
 16. Thecompound of claim 1, wherein each R₆ is independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroalicyclyl, hydroxy,halogen, sulfonyl, perhaloalkyl, —CN, —OR₅, —NR₅R_(5a),—NR₅NR_(5a)R_(5b), —NR₅N═CR_(5a)R_(5b), —N(R₅)C(R_(5a))═NR_(5b),—C(═Z)R₅, —C(═Z)OR₅, —C(═Z)NR₅R_(5a), —N(R₅)—C(═Z)R_(5a),—N(R₅)—C(═Z)NR_(5b)R_(5a), —OC(═Z)R₅, —N(R₅)—S(═O)₂R_(5a), and —SR₅. 17.The compound of claim 1, wherein each R₆ is independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,cycloalkenyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heteroalicyclyl,hydroxy, halogen, —OR₅, and —NR₅R_(5a).
 18. The compound of claim 1,wherein each R₆ is independently hydrogen or alkyl.
 19. The compound ofclaim 1, wherein R₂, R_(2a), R_(2b), and _(R2c) are separately selectedfrom the group consisting of hydrogen, C₁-C₅ straight chained orbranched alkyl, F, Cl, Br, perhaloalkyl, —CN, —OR₅, and —C(═O).
 20. Thecompound of claim 1, wherein R₂, R_(2a), R_(2b), and R_(2c) are hydrogenor C₁-C₅ straight chained or branched alkyl.
 21. The compound of claim1, wherein R₂, R_(2a), R_(2b), and R_(2c) are each hydrogen.
 22. Acompound of formula II:

or a pharmaceutically acceptable salt or prodrug thereof, wherein: n is3; R₁ is hydrogen; R₂, R_(2a), R_(2b), R_(2c), and each R₆ are hydrogen;each Y is methylene or oxygen, wherein at least one Y is oxygen; and Ais a substituted aryl.
 23. The compound of claim 19, wherein A issubstituted with fluoro. 24.4-(2-(2-fluorophenyl)tetrahydro-2H-pyran-2-yl)phenol.
 25. Apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula II, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier, excipient, ordiluents, wherein the compound of Formula II has the structure:

wherein: n is an integer selected from the group consisting of 1, 2, 3,4, 5 and 6; R₁ is selected from the group consisting of hydrogen, C₁-C₈straight chained or branched alkyl, C₁-C₈ straight chained or branchedalkenyl, cycloalkyl, cykloalkenyl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aryl, substituted orunsubstituted heteroalicyclyl, sulfonyl, C₁-C₈ straight chained orbranched perhaloalkyl, —C(═Z)R₅, —C(═Z)OR₅, —C(═Z)N(R₅)₂,—S(═O)₂NR_(5a)R_(5b), —P(═O)(OR₅)₂, and —CH₂OC(═O)R₅; R₂, R_(2a),R_(2b), R_(2c), and each R₆ are separately selected from the groupconsisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroalicyclyl, hydroxy,halogen, sulfonyl, perhaloalkyl, —CN, —OR₅, —NR₅R_(5a),—NR₅NR_(5a)R_(5b), —NR₅N═CR_(5a)R_(5b), —N(R₅)C(R_(5a))═NR_(5b),—C(═Z)R₅, —C(═Z)OR₅, —C(═Z)NR₅R_(5a), —N(R₅)—C(═Z)R_(5a),—N(R₅)—C(═Z)NR_(5b)R_(5a), —OC(═Z)R₅, —N(R₅)—S(═O)₂R_(5a), and —SR₅;each Y is separately selected from the group consisting of methylene,methylene substituted with one or two R₆ groups, sulfur, oxygen, C═O,unsubstituted nitrogen, and nitrogen substituted with a substituentselected from the group consisting of hydrogen, unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heteroalicyclyl, wherein the alkyl, when substituted, isnot substituted with phenyl; provided that the ring defined by the Ygroups is not a 4-substituted piperidine, and provided that when thering defined by the Y groups is 2,6-dioxane, where position 1 of thedioxane is the position to which the A group is attached, then A is asubstituted aryl, and provided that when one Y is oxygen, a second Y isC═O, and a third Y is nitrogen, then the combination of oxygen, C═O, andnitrogen forms an oxazinanone two Y groups are optionally bound togetherto form a substituted or unsubstituted C₁-C₉ cycloalkyl or C₁-C₉heteroalicyclyl; R_(2a) is optionally bound to one Y group to form asubstituted or unsubstituted C₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, orC₄-C₉ cycloalkenyl; any bond represented by a dashed and solid linerepresents a bond selected from the group consisting of a single bondand a double bond; A is selected from the group consisting ofsubstituted heteroaryl, unsubstituted heteroaryl, substitutedheteroalicyclyl, unsubstituted heteroalicyclyl, unsubstitued aryl, andsubstituted aryl, wherein the heteroaryl is selected from the groupconsisting of furan, thiophene, phthalazinone, pyrrole, oxazole,thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole,thiadiazole, pyran, pyridine, pyridazine, pyrimidine, and pyrazine; A isoptionally bound to one Y group to form a substituted or unsubstitutedC₄-C₉ heteroalicyclic, C₄-C₉ cycloalkyl, or C₄-C₉ cycloalkenyl; Z isoxygen or sulfur; and each R₅, R_(5a) and R_(5b) are separately selectedfrom the group consisting of hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, and substituted orunsubstituted heteroalicyclyl; provided that when every Y is asubstituted or unsubstituted methylene, then A is not a substituted orunsubstituted aryl; and provided that A and the ring defined by the Ygroups and the carbon atom to which they are attached are not bothsimultaneously carbocyclic rings or heterocyclic rings.